肿瘤领域文献阅读汇编

Benefits of healthy diets for type 2 diabetes (T2D) prevention are established. It remains unclear whether such recommendations should be tailored to specific subgroups according to their susceptibility to the disease. This study aimed to assess whether the association of diet quality with T2D risk differs across subgroups with different genetic or epigenetic susceptibility. We used data from a case-cohort within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (random subsample with genetic data of 2204 participants, 750 verified incident T2D cases; random subsample with epigenetic data of 1065 participants, 676 verified incident T2D cases). The Alternative Healthy Eating Index (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH), Dietary Inflammatory Index (DII) and the Mediterranean Diet Pyramid score (MedPyr) were used to assess diet quality. A blood DNA methylation risk score (MRS) was used to reflect epigenetic risk. Genetic risk was characterized using global polygenic risk scores (PRS) and pathway-specific polygenic risk scores (pPRS). Cox proportional hazards models were used to assess the modification of the diet quality-diabetes risk association by the risk scores. Higher adherence to the AHEI-2010 was associated with a lower risk of T2D, while higher MRS, PRS and pPRS predictably indicated higher risk in this population. We detected significant modification of the diet quality-T2D association by the MRS for AHEI-2010 (p = 0.008) and MedPyr (p < 0.0001) and DII (p = 0.010) but only the AHEI-2010 × MRS interaction was robust across all sensitivity analyses. However, we did not find evidence of interaction between diet quality and genetic risk. The associations of healthy diets with T2D could depend on the diabetes risk captured by blood DNA methylation profiles, but they do not seem to depend on the genetic predisposition for T2D. Confirmation of the effect modification by the MRS in independent populations is further required before considering clinical application.

Teclistamab, a B cell maturation antigen-targeting bispecific antibody, has demonstrated substantial activity in relapsed multiple myeloma (MM), particularly in earlier lines of therapy, and may have higher efficacy in high-risk smoldering MM (HR-SMM) with a more functional immune system. In the randomized phase 2 ImmunoPRISM trial, we compared fixed-duration teclistamab with lenalidomide-dexamethasone (Rd) in HR-SMM. After a six-patient safety run-in, patients were randomized 2:1 to teclistamab or Rd. The primary endpoint was complete response (CR) rate. As of 26 May 2026, 59 patients were treated-45 received teclistamab and 14 received Rd. Teclistamab treatment induced a CR in 77.8% patients versus 0% with Rd, and minimal residual disease negativity at 10-5 in 82.2% patients. At a median follow-up of 24.5 months, 2-year progression-free survival was 92% with teclistamab versus 49% with Rd. Overall, response rates, duration of response and time to progression (TTP) were significantly improved in teclistamab compared to Rd. Toxicities in the teclistamab arm included grades 1-2 cytokine release syndrome, no neurotoxicity and no increase in grade 3 infections compared to Rd (20% versus 21%). No deaths occurred in either arm. Teclistamab represents a highly active immune-interception strategy for HR-SMM. ClinicalTrials.gov registration: NCT05469893 .

Intratumoral heterogeneity (ITH) is thought to contribute to tumour evolution and treatment resistance but its biological and clinical significance in localised head and neck squamous-cell carcinoma (HNSCC) remains incompletely understood. In the prospective SCANDARE study, we analysed 87 patients with resectable HNSCC treated with upfront surgery. Two to five spatially distinct tumour regions per patient underwent pathological evaluation, targeted DNA sequencing, and bulk RNA sequencing. Genomic ITH (gITH) was quantified using clonal deconvolution and Shannon diversity indices, whereas transcriptional heterogeneity (tITH) was assessed using the intratumour expression distance metric. Associations between ITH, molecular features, tumour microenvironment composition, and clinical outcomes were explored using multivariable statistical models. Pathology-based spatial heterogeneity showed limited prognostic value. gITH was common, with 37% of tumours displaying regionally heterogeneous pathogenic variants, including spatially actionable alterations in 10% of patients. In an initial multivariable Cox model, higher gITH was associated with shorter disease-free survival. However, after Ridge-penalised modelling and bootstrap internal validation, the effect size was attenuated [corrected hazard ratio 1.42, 95% confidence interval (CI) 0.91-2.75]. The overall model retained moderate discriminative performance (optimism-corrected C-index 0.69, 95% CI 0.59-0.79). gITH was associated with tumour cellularity, reduced estimated endothelial cell infiltration, and alterations in KMT2C and PIK3CA. tITH differed according to human papillomavirus (HPV) status, with lower tITH in HPV-positive tumours, and was associated with distinct biological pathways and genomic alterations. Genomic and tITH were not correlated. This prospective multiregion study provides a comprehensive characterisation of genomic and tITH in localised HNSCC. Our findings highlight substantial spatial molecular diversity within primary tumours and suggest potential associations between heterogeneity, tumour biology, and clinical outcome that warrant validation in independent cohorts.

B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common form of paediatric cancer and is characterised by the clonal expansion of immature B lymphocytes. The advent of targeted therapies has transformed BCP-ALL from a largely fatal disease to one which is well managed under current protocols. Continued refinements to disease classification have facilitated the identification of novel drug targets that underscore much of this change. Despite this progress, some patients remain unclassified by current conventions, and have not profited from the era of targeted therapy. Relapsed disease likewise remains a major challenge, and although new immunotherapies have gone a long way, additional strategies are needed. Addressing these issues requires a concerted effort to identify novel drug targets. Here, we discuss the origins and classification of BCP-ALL, before outlining the therapeutic advances that have considerably improved disease outlook over the last few decades. We then outline the latest trends in disease treatment, and propose how recent discoveries may translate into new therapeutic approaches.

Cancer progression is driven by spatially organised intratumoural heterogeneity, yet the molecular basis of this organisation remains incompletely understood. While spatial transcriptomics has advanced rapidly, the spatial architecture and functional relevance of tumour lipid metabolism remain poorly characterised. We aimed to resolve whether membrane phospholipid remodelling is spatially organised across epithelial cell states in human colon cancer. We developed an integrative spatial multi-omic strategy linking mass spectrometry imaging to transcriptome-defined cellular states on consecutive tissue sections from primary and intraperitoneal metastatic human colon cancer specimens. Epithelial lipid phenotypes were characterised, validated in an independent cohort, and linked to transcriptional programmes. We identified four spatially organised epithelial lipid phenotypes defined by membrane phospholipid composition. These phenotypes aligned with transcriptional programmes reflecting epithelial lineage and differentiation state, and were organised along a differentiation axis marked by coordinated remodelling of arachidonic acid-, oleic acid-, and linoleic acid-containing phospholipids. Secretory-associated states, enriched in metastatic lesions, showed increased DHA-containing phospholipids and activation of peroxisomal pathways. Lipid phenotype assignments were reproducible across an independent cohort. Membrane phospholipid composition encodes biologically meaningful epithelial cell states within human tumours, establishing lipid remodelling as a structured and spatially organised dimension of tumour heterogeneity. This study was supported by the ISCIII (PI19/00002, PI24/00313), the Health Research Institute of the Balearic Islands (IMP22/04), the Government of the Balearic Islands (AP_2021_001), the Basque Government (IT1491-22), the European Regional Development Fund, and the Scientific Foundation, Spanish Association Against Cancer (INVES222995RODR).

Idecabtagene vicleucel (ide-cel) induces deep responses in relapsed/refractory multiple myeloma, yet more than half of patients relapse within 1 year. The intrinsic features of chimeric antigen receptor T-cell (CAR-T) products that distinguish durable from nondurable responders are poorly defined, particularly at single-cell resolution, and defining drivers of durable response is critical to guide patient counseling and to inform strategies for optimizing CAR-T manufacturing and efficacy. To address this need, 40 ide-cel infusion products (184 398 cells) were profiled using single-cell RNA sequencing. These analyses revealed that a transcriptional program in CD4 CAR-T cells that led to durable responses is characterized by NF-κB signaling, prosurvival circuits, tonic/chemokine signaling, and elevated CAR transgene expression. These features were associated with prolonged progression-free and overall survival irrespective of baseline clinical characteristics. Further, analyses of paired apheresis and tumor microenvironment samples showed that elevated NF-κB activity is an intrinsic hallmark of T-cell fitness that is characterized by a central memory phenotype and the lack of checkpoint receptor expression, and that these features were manifest in marrow-derived and peripheral blood T cells before CAR-T manufacturing. Finally, validating functional relevance, the pharmacologic inhibition of NF-κB abrogated CAR-T cytotoxicity and cytokine production in vitro. Our results support that NF-κB in the ide-cel product marks a signaling axis affecting CAR-T function and that NF-κB activity represents a global marker of T-cell fitness present before CAR-T manufacture.

We present 5-year survival results in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) from TRANSCEND NHL 001 (TRANSCEND), including data from the separate long-term follow-up (LTFU) study. Overall, 345 patients were leukapheresed and 270 received lisocabtagene maraleucel (liso-cel). Among 257 patients who were efficacy-evaluable, median overall survival (OS) was 27.5 months (95% confidence interval [CI], 16.2-47.3; leukapheresed set: 15.2 months; 95% CI, 11.5-23.4); estimated 5-year OS was 38% (95% CI, 32-45; leukapheresed set: 33%; 95% CI, 28-39). Median disease-specific survival (DSS; excludes deaths unrelated to disease progression) was 67.8 months (95% CI, 23.5 to not reached [NR]; leukapheresed set: 27.4 months; 95% CI, 14.4-69.7]); estimated 5-year DSS was 52% (95% CI, 45-59; leukapheresed set: 47%; 95% CI, 41-52). Among patients from TRANSCEND who were efficacy-evaluable, alive at study completion, and enrolled in the LTFU (n = 84), median OS and DSS were NR (95% CI, NR to NR); estimated 5-year OS and DSS were 78% (95% CI, 67-86) and 92% (95% CI, 84-97), respectively. Most deaths occurred ≤2 years after infusion; no new safety signals were observed with low rates of late severe infections and second primary malignancies. These data support the curative potential of liso-cel in patients with R/R LBCL. This trial was registered at www.clinicaltrials.gov as NCT02631044 and NCT03435796.

Current clinical methods for detecting low-abundance PML::RARα fusion and drug-resistant single-base mutations face significant challenges, highlighting the urgent need for a rapid, sensitive, cost-effective genetic detection method for diagnosing acute promyelocytic leukemia. The CRISPR/Cas12a system has emerged as a revolutionary tool in nucleic acid detection. However, its applications are frequently constrained by the requirement for protospacer adjacent motifs (PAMs). In this study, we demonstrated that a moderate temperature increase enhanced CRISPR/Cas12a activity while allowing the use of atypical suboptimal PAMs. Utilizing a PCR-driven, suboptimal PAM-dependent CRISPR/Cas12a cascade, we sensitively detected the BCR1-type PML::RARα fusion with a detection limit of 0.1 aM. This method effectively identified low-abundance mutant cells in the presence of wild-type cells and demonstrated its efficacy in detecting minimal residual disease samples from patients with relapsed acute promyelocytic leukemia. Additionally, we developed a sensitive approach for detecting L217F single-base mutations using a cascade strategy of polymerase chain reaction, ligase chain reaction and CRISPR/Cas12a, achieving a detection limit of 10 aM in various wild-type DNA samples. Consequently, these methods hold considerable promise for the rapid diagnosis of acute promyelocytic leukemia, the sensitive detection of and the low-abundance drug-resistance nucleic acid mutations.

Accurate prediction of pathological complete response (pCR) following neoadjuvant therapy is crucial for personalized treatment planning in patients with locally advanced rectal cancer (LARC). This study aimed to explore the application of 3D transrectal ultrasound (TRUS) for this purpose. In this study, 538 LARC patients from five hospitals were enrolled and divided into training (n = 348), internal validation (n = 87), and external validation (n = 103) cohorts. Using pretreatment 3D TRUS data of the rectal tumors, a deep learning framework comprising an automated segmentation model and a pCR prediction model was constructed and validated. The segmentation model achieved an excellent Dice score of 0.89. The predictive model, when trained on data sampled at 9° or 18° intervals, yielded area under the curve (AUC) values of 0.92 (internal validation) and 0.85-0.86 (external validation), with accuracies of 86.2%-90.8% and 81.6%-83.5%, respectively; decision-curve analysis also demonstrated clinically meaningful net benefits. This study presents the first deep learning framework based on 3D TRUS for pCR prediction in LARC patients, offering an automated and reproducible tool that may support clinical decision-making in rectal cancer management. However, further validation in larger, multi-device cohorts is essential before clinical application.

Oral bacteria are swallowed constantly but rarely dominate the gut. In this issue of Cell Host and Microbe, Jang et al.1 turn that leakage into a measurement, showing that mouth-to-gut transmission rises specifically in gastrointestinal cancers and carries a diagnostic signal readable from saliva alone.

Indonesia faces 3 interlocking medical workforce crises: an absolute specialist deficit projected to reach 70,000 by 2032 (national density of 0.18 per 1000 population vs the Ministry of National Development Planning [Bappenas] target of 0.28), severe maldistribution (with nearly 59% of specialists concentrated in Java), and a structural anomaly in which residents pay tuition while performing essential clinical work. The 2023 Health Law (Law 17/2023) authorized a transformative reform: a hospital-based residency pathway (Rumah Sakit Pendidikan Penyelenggara Utama [primary teaching hospital; RSPPU]) operating in parallel with the long-established university-based system. This study aimed to examine the rationale, policy design, and early implementation of Indonesia's dual hospital-university specialist medical education reform, interpreted through an 8-step change management framework developed by Kotter, and to identify transferable lessons for low- and middle-income countries. We conducted an integrative qualitative policy process review combining two evidence streams: (1) systematic documentary analysis of 19 source documents (17 primary legal, regulatory, and policy instruments plus 2 interministerial joint monitoring site-visit reports) and (2) engagement of 34 key informants through semistructured interviews and focus group discussions (45-120 min), comprising policymakers, collegium representatives, hospital leaders, and residents across all 6 pilot sites, recruited purposively until thematic saturation. Interview and focus group data were analyzed using a hybrid deductive-inductive thematic approach with an 8-step change management framework developed by Kotter as an a priori coding frame, and member checking was completed with 7 of the 34 informants. The reform designated 6 top-tier national referral hospitals as RSPPUs and enrolled 52 residents from 412 applicants (an acceptance rate of 12.6%) across 6 high-need specialties (ophthalmology, cardiology, pediatrics, orthopedics, neurology, and oncology). All 6 pilot sites established functional education units and designated institutional officials, adopted dual accreditation, and operationalized an integrated e-logbook for competency tracking, real-time monitoring of 80-hour duty limits, and anonymous bullying reporting. An interministerial joint monitoring team visited all 6 sites and scored each site as satisfactory or better across governance, curriculum, faculty, infrastructure, and learner support. Four cross-cutting themes emerged: financial-barrier removal, dual-governance pragmatism, accreditation strain, and equity-anchored deployment. Persistent tensions include variable educator compensation across hospitals; however, a standardized national framework remains under development. Mapping to the framework developed by Kotter demonstrated strong evidence for steps 1 to 6 and early evidence for steps 7 to 8. Indonesia's dual hospital-university residency model is a scalable, equity-oriented, and competency-based reform that is operationally feasible and globally aligned in its early implementation. While long-term effectiveness and sustainability await longitudinal evaluation, the design offers a transferable, not yet definitively replicable, template for low- and middle-income countries confronting parallel workforce crises.

Artificial intelligence (AI) has become a pivotal driver of innovation in cancer immunotherapy through large-scale biological data modeling, multimodal information integration, and advanced machine learning approaches. At the AACR Annual Meeting 2026, AI-based frameworks demonstrated broad applications across the immunotherapy continuum, including response prediction, patient stratification, neoantigen identification, and therapeutic development. An array of studies has transcended conventional single-biomarker paradigms, leveraging multimodal clinical and molecular datasets to construct biologically interpretable representations of tumor-immune ecosystems. Taken together, these advances signal a shift from reductionist biomarker-based prediction toward integrative, data-driven precision immunotherapy, fundamentally reshaping therapeutic stratification and target discovery and establishing artificial intelligence as a central driver of the conceptual and practical transformation of cancer immunotherapy.

The therapeutic paradigm in oncology is undergoing a profound transformation driven by antibody-drug conjugates (ADCs) and bispecific antibodies (bsAbs). This review comprehensively summarizes recent clinical advances of these platforms across both hematologic malignancies and solid tumors. ADCs such as trastuzumab deruxtecan have expanded the concept of targetable HER2 expression, demonstrating meaningful intracranial activity and redefining standards of care in HER2-low breast cancer and beyond. The landscape continues to broaden with novel ADC targets (TROP2, CLDN18.2, B7-H3, HER3) and bispecific ADC constructs. Concurrently, T‑cell-engaging bsAbs-CD20×CD3 in B‑cell lymphomas, BCMA×CD3 and GPRC5D×CD3 in multiple myeloma, and CD19×CD3 in acute lymphoblastic leukemia-have achieved deep and durable responses in heavily pretreated populations. In solid tumors, EGFR‑MET and DLL3‑targeted bsAbs have delivered clinically validated efficacy in historically refractory settings, including regulatory approval of tarlatamab. Despite these successes, critical challenges persist, including the management of unique toxicity profiles, the emergence of resistance via antigen escape and T‑cell exhaustion, and the absence of validated predictive biomarkers. Optimal sequencing of these agents with one another and with chimeric antigen receptor T‑cell therapy remains largely empirical. Next‑generation strategies-bispecific ADCs, probody‑drug conjugates, and immune‑stimulating antibody conjugates-combined with immunotherapy partnerships hold promise for overcoming resistance and improving therapeutic indices. By distilling pivotal clinical data and highlighting unresolved questions, this review provides a roadmap for translating antibody‑based innovations into precision oncology.

Prostate cancer (PCa) patients are at increased fracture risk due to the need for androgen deprivation therapy (ADT) and progressive bone metastases. Previous meta-analyses of randomised controlled trials suggest that androgen receptor pathway inhibitors (ARPIs) increase fracture risk. We assessed the impact of abiraterone-based treatment intensification on fracture-related hospitalisation (FRH) within the STAMPEDE trial platform. We performed a secondary analysis of two STAMPEDE trials in patients with high-risk non-metastatic (M0) or metastatic (M1) disease. Patients were allocated to either standard of care (SOC) or SOC plus abiraterone with prednisolone (AAP) or, in a later comparison, SOC+AAP with enzalutamide (Enza). A prespecified coding framework within Hospital Episode Statistics (HES) identified FRHs. Flexible parametric competing-risk models estimated 5-year cumulative incidence of FRH and sub-distribution hazard ratios (SDHR), with death as a competing risk. Between Nov 2011 and Mar 2016, 3893 patients were randomised to the STAMPEDE AAP±Enza trials. Linked HES data were available for 3102 patients in England. In M1 disease, 5-year FRH incidence was significantly lower with SOC + AAP than SOC alone (22% vs 30%; SDHR 0.77, 95%CI 0.59-0.99; p = 0.04) and with SOC + AAP + Enza than SOC alone (28% vs 38%; SDHR 0.69, 95%CI 0.54-0.88; p = 0.002). No significant difference was observed in M0 patients. Limitations include potential under-estimation of total fracture burden by exclusion of non-hospitalised fractures, lack of baseline assessment of fracture risk including bone mineral density, and longitudinal use of bone-protective therapy. Abiraterone-based treatment intensification did not increase FRH compared to SOC alone. In M1 disease, abiraterone reduced rather than augmented fracture risk, most plausibly reflecting improved metastatic bone disease control.

Daily witnessed ingestion in community-based pharmacies is standard practice for methadone maintenance treatment for opioid use disorder in British Columbia, Canada. Whether this practice, compared with take-home methadone, may pose a barrier to sustained retention in treatment and its lifesaving benefits is not known. To assess the different initiation times of methadone take-home doses in terms of time to all-cause mortality and methadone discontinuation, defined as a gap in prescribed doses lasting 5 or more days. This cohort study using principles of target trial emulation used observational data from British Columbia, Canada, 2010-2022. Both incident (no history of opioid agonist treatment [OAT]) and prevalent new-user (no OAT within the past month) designs were used. The study included individuals aged 18 years or older who completed OAT induction, were not pregnant or incarcerated, and had no history of cancer treatment or palliative care. Data analyses were conducted from March 5, 2025, to May 29, 2026. Exposure strategies were (1) no take-home dosing, (2) take-home dose initiation within 0 to 4 weeks after completing induction, (3) take-home dose initiation within 5 to 12 weeks after completing induction, (4) take-home dose initiation within 13 to 24 weeks after completing induction, and (5) take-home dose initiation within 25 to 52 weeks after completing induction. Outcomes were time to all-cause mortality and methadone discontinuation. A clone-censor-weight approach was used to estimate the 78-week adjusted risk difference (ARD). A total of 9788 incident users (median age, 34.1 [IQR, 27.2-44.1] years; 32.8% female) and 31 658 prevalent new users (median age, 36.9 [IQR, 29.7-46.2] years; 33.3% female) were included. Compared with no take-home dosing in prevalent new-user analysis, ARDs for the mortality outcome were -0.87 (95% CI, -1.51 to -0.23) for take-home dose initiation within 0 to 4 weeks after completing induction, -0.98 (95% CI, -1.62 to -0.33) for take-home dose initiation within 5 to 12 weeks after completing induction, -0.82 (95% CI, -1.59 to -0.06) for take-home dose initiation within 13 to 24 weeks after completing induction, and -0.31 (95% CI, -1.05 to 0.44) for take-home dose initiation within 25 to 52 weeks after completing induction. Compared with no take-home dosing in prevalent new-user analysis, the discontinuation outcome ARDs were -2.04 (95% CI, -3.99 to -0.10) for take-home dose initiation within 0 to 4 weeks after completing induction, -5.29 (95% CI, -6.82 to -3.76) for take-home dose initiation within 5 to 12 weeks after completing induction, -5.97 (95% CI, -7.16 to -4.78) for take-home dose initiation within 13 to 24 weeks after completing induction, and -4.39 (95% CI, -5.37 to -3.42) for take-home dose initiation within 25 to 52 weeks after completing induction. Similar patterns were observed among incident users. Multiple sensitivity analyses with sample restrictions, time-0 classifications, timeline restrictions, and addressing residual confounding bias supported the primary results. Results of this study suggest that initiating take-home methadone within 5 to 12 weeks and 13 to 24 weeks after completing induction resulted in the greatest benefits in reducing mortality and treatment discontinuation, although any take-home dosing was consistently better than no take-home dosing. These client-level benefits warrant consideration when refining clinical guidelines on take-home dosing.

The 1959 World Health Organization (WHO) definition of anemia is widely used, but its relationship with mortality in the general adult population is uncertain. To evaluate associations between baseline hemoglobin concentration and long-term mortality by age and sex. Prospective cohort study. Population-based cohort in the United Kingdom. 502 188 adults (median age, 58 years; 54.4% women) recruited from 2006 to 2010; hemoglobin concentration was measured in 477 876 (95.2%). Analyses were stratified by sex and age (<60 vs. ≥60 years). Median follow-up was 13.6 years. Hemoglobin concentration categorized relative to WHO sex-specific thresholds (men, <13.0 g/dL; women, <12.0 g/dL). Outcomes were all-cause, cardiovascular, and cancer mortality. All-cause mortality showed a U-shaped association with hemoglobin concentration, with lowest risk 1 to 3 g/dL above the WHO threshold. In the primary adjusted model, the 10-year standardized cumulative incidence (SCI) was 4.5% in the reference group versus 12.5% among participants more than 2 g/dL below the threshold (absolute risk difference [ARD], +8.1 percentage points; 95% CI, 6.7 to 9.4 percentage points); over the entire follow-up, the adjusted hazard ratio (HR) was 2.87 (CI, 2.54 to 3.25). Among those 0 to 1 g/dL above the threshold, the 10-year SCI was 5.3% (ARD, +0.8 percentage points; CI, 0.7 to 1.0 percentage points) and the adjusted HR was 1.18 (CI, 1.15 to 1.21). Associations were less consistent in women younger than 60 years. Patterns for cardiovascular and cancer mortality were similar at low and borderline concentrations but attenuated at higher concentrations. Single baseline hemoglobin concentration measurement; predominantly White population. Mortality was lowest at hemoglobin concentrations 1 to 3 g/dL above current WHO thresholds, with higher mortality below and above this range. These hypothesis-generating findings should not define new thresholds but may inform clinical interpretation and evaluation of borderline hemoglobin concentration values. None.

Although weekend warrior physical activity is linked to lower mortality in the general population, whether it confers similar benefits among individuals with cardiovascular disease (CVD) remains unknown. This study aimed to investigate the association between the weekend warrior activity pattern and mortality in patients with CVD. We performed a sub-cohort analysis of 8128 UK Biobank participants with CVD. Physical activity patterns were defined by weekly moderate-to-vigorous physical activity (MVPA) volume and distribution: weekend warrior (≥150 min/week MVPA, with ≥50% accumulated on 1-2 days), regularly active (≥150 min/week MVPA spread over >2 days), and inactive (<150 min/week MVPA). Outcomes were all-cause, CVD-specific, and cancer-specific mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for mortality across activity patterns. Of the participants, 3004 (44.09%) were weekend warriors, 1540 (18.95%) were regularly active, and 3584 (36.96%) were inactive. Over a median follow-up of 7.85 years, 881 deaths occurred. Compared with the inactive pattern, both weekend warrior (HR, 0.61; 95% CI: 0.52-0.71) and regularly active (HR, 0.68; 95% CI: 0.56-0.82) patterns were associated with lower risks of all-cause mortality among participants with CVD. Similar associations were observed for CVD- and cancer-specific mortality. Among individuals with CVD, the weekend warrior pattern was associated with a lower risk of mortality, with survival benefits comparable to those observed for the regularly active pattern. This pattern may serve as a practical alternative for patients who have difficulty maintaining regular activity across the week.

The aim of this study was to evaluate associations of muscle-strengthening activity (MSA) with all-cause, cardiovascular disease (CVD), and cancer mortality in adults with diabetes, independent of and jointly with moderate-to-vigorous aerobic physical activity (MVPA). This prospective cohort study included 29 609 adults with diabetes free of CVD and cancer from the US National Health Interview Survey 1997-2018 (baseline). Muscle-strengthening activity and MVPA were derived from standardized questionnaires. Mortality by 2019 was ascertained through linkage to the National Death Index. Cox models were utilized to estimate adjusted hazard ratios (aHRs). Over 270 178 person-years, 6716 all-cause, 1995 CVD, and 1202 cancer deaths were documented in the study population (mean age, 55.7 years, 51.6% female). There were U-shaped associations of MSA with all-cause mortality risk, with ≤ 3 times/week associated with mortality benefits. Compared with no MSA, aHRs of all-cause mortality were 0.72 (95% confidence interval, 0.47-1.10) for MSA < 1 time/week, 0.58 (0.44-0.77) for 1 time/week, 0.76 (0.61-0.96) for 2 times/week, 0.80 (0.67-0.96) for 3 times/week, 0.97 (0.65-1.47) for 4-6 times/week, and 0.99 (0.83-1.19) for ≥ 7 times/week. Non-linear associations with CVD and cancer mortality were also observed. These associations did not vary by age or sex. Jointly, compared with no MSA and MVPA < 150 min/week, adults performing MSA ≤ 2 times/week and MVPA ≥ 150 min/week had the lowest all-cause and CVD mortality risk. For adults with diabetes, performing MSA ≤ 3 times/week may be associated with lower all-cause, CVD, and cancer mortality risk, independent of MVPA. Jointly performing MSA ≤ 2 times/week and MVPA ≥ 150 min/week may confer the lowest all-cause and CVD mortality risk.

Radiocesium in food poses an ongoing challenge in environmental health risk assessment. Annual dose compliance (1 mSv/year) is essential for radiological protection but may not reflect cumulative lifetime cancer risk (LCR) under chronic exposure or corresponding public risk perceptions. We developed an integrated radiological risk assessment framework to evaluate dietary radiocesium-related health risks and determine whether these estimates align with public risk perceptions. We estimated prefecture-level LCR and risk-perception gaps through multilevel regression and poststratification using a nationwide survey in Japan, together with food-monitoring data on radiocesium concentrations. The annual dietary radiation dose was well below the 1 mSv/year benchmark, while modeled mortality and morbidity LCRs remained above 10-5, ranging from 1.84 × 10-5 to 1.37 × 10-4 and from 2.70 × 10-5 to 2.02 × 10-4, respectively. The high-risk prefectures, particularly in Tohoku identified in spatial analyses, warrant prioritized monitoring. Agricultural products were the dominant exposure pathway, accounting for approximately 55.0-64.5% of the estimated LCR. Estimated risk tended to exceed perceived risk in northern Japan, indicating a need for proactive risk control, whereas perceived risk tended to exceed estimated risk in central Japan, suggesting a greater need for targeted communication. Our framework supports region-specific monitoring and communication by considering the LCR alongside annual dose metrics.

Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their clinical and functional significance in chronic myeloid leukemia (CML) remains incompletely defined. Here, we show that a distinct mtDNA mutational landscape is associated with mitochondrial metabolic programs and response to imatinib therapy in CML. We performed comprehensive profiling of somatic mtDNA mutations in 120 patients with chronic-phase CML. At diagnosis, 241 somatic mtDNA mutations were identified in 92 patients, including 29 homoplasmic mutations. In a clinically annotated cohort of 79 imatinib-treated patients, a higher number of mtDNA mutations (≥3 mutations) and higher variant allele frequency were associated with superior molecular responses, and remained significant in multivariable analyses. mtDNA mutational patterns were associated with distinct metabolic phenotypes in CD34+ leukemic stem/progenitor cells. Suboptimal responders exhibited increased mitochondrial respiration, spare respiratory capacity, mitochondrial content, and enrichment of mitochondrial biogenesis and lipid metabolic programs, consistent with enhanced oxidative phosphorylation dependence. In contrast, favorable responders displayed higher mtDNA mutational burden together with reduced respiratory reserve and increased mitophagy-related programs. Pharmacologic Complex I inhibition reduced clonogenic potential and enhanced imatinib sensitivity. Collectively, these findings identify mtDNA mutational states as a biomarker of metabolic fitness and therapeutic response in CML, while supporting further investigation of mitochondrial metabolism as a potential therapeutic vulnerability in CML.

Long-term efficacy data supporting the use of reduced-dose radiotherapy (rdRT) alone for intracranial pure germinoma remain limited. In this study, we evaluated the long-term efficacy and safety of rdRT alone in patients with this condition. We retrospectively analyzed the data of 139 patients with intracranial pure germinoma treated with RT alone, using whole-ventricle irradiation (73.6%), whole-brain irradiation (9.3%), or craniospinal irradiation (CSI, 17.1%). Patients who had M+ disease were included, whereas those treated with local RT alone were excluded. The most commonly prescribed dose to gross tumors was 30.0-30.6 Gy delivered in 15-17 fractions (median total dose, 35.5 Gy). The median extended-field (whole-ventricle, whole-brain, or craniospinal) dose was 23.4 Gy. Survival outcomes were analyzed according to total RT dose, whole-ventricle dose, RT field, and disease distribution. At a median follow-up of 102 months, the 5- and 10-year event-free survival (EFS) rates were 90.0% and 88.4%, respectively, and the corresponding overall survival rates were 100.0% and 98.4%. Dose escalation beyond 30.6 Gy did not improve EFS (P = 1.000). A whole-ventricle dose of 18 Gy was not associated with inferior EFS compared with >18 Gy (P = 0.155). In patients with bifocal disease (suprasellar and pineal, n = 24), CSI significantly improved 5-year EFS (100.0% vs. 63.3%, P = 0.040). In the study-defined optimal RT group (total dose ≥30 Gy, excluding bifocal disease without CSI; n = 125), the 3- and 5-year EFS rates were 94.2% and 92.4%, respectively. No grade ≥3 acute or late RT-related toxicities or secondary malignancies were observed. RdRT alone, administered with an appropriate dose and RT field according to disease status, provided excellent long-term tumor control with minimal toxicity. Tumor and extended-field doses of 30.6 Gy and 18 Gy, respectively, appeared adequate. A prospective phase 2 trial is planned to further validate this treatment strategy.

Ovarian cancer is the most lethal gynecological malignancy and lacks therapeutic options in the recurrent setting. We previously determined the safety and initial clinical activity of intraperitoneal autologous monocytes with interferon gamma and interferon alpha (AMIGA) in women with recurrent, platinum-resistant ovarian cancer, but not all enrolled patients showed benefit, warranting further analysis to understand and improve this therapy. Bulk RNA sequencing and single-cell RNA sequencing were conducted on circulating immune cells from patients with ovarian cancer treated with AMIGA. Primary human monocytes and T cells were isolated from healthy donors and used in co-cultures with ovarian cancer cell lines to test the effects of AMIGA on T-cell recruitment. Comparing circulating immune cells from long-term responders to non-responders from our clinical trial revealed an increased cell-mediated immune response in long-term responders. T cells in AMIGA-treated patients also upregulated unique, specific T cell receptor-beta chain genes. Bulk RNA-seq of peripheral blood mononuclear cells revealed AMIGA-driven upregulation of CXCL10 and CCL2 mRNA. An increase in these chemokines was consistently reflected in patients' malignant ascites. Finally, in vitro models validated increases in CXCL10 as well as CCL2, and demonstrated that these chemokines exert variable effects on T-cell chemotaxis. The AMIGA-driven effects on T cell recruitment and upregulation of specific T cell receptor-beta chain genes support the development of future combination therapies of intraperitoneal AMIGA and T cell-based immunotherapies.

SAR443216 is an engineered human trispecific antibody that targets human epidermal growth factor receptor 2 (HER2)-positive (HER2+) cancer cells and activates T cells via co-engagement of cluster of differentiation (CD)3 and CD28. This first-in-human, dose-escalation study evaluated the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics of SAR443216 in participants with relapsed/refractory (R/R) HER2-expressing solid tumors. In this multicenter, open-label, non-randomized Phase 1 study (NCT05013554), SAR443216 was administered intravenously at dose levels (DLs) of 18-900 µg. Dose escalation occurred within participants using intraparticipant lead-in dosing (2-week and 3-week lead-in cohorts). The primary objective was to determine the maximum tolerated dose (MTD); secondary objectives included PK, immunogenicity, and preliminary clinical activity. 40 participants (n≥3 at each DL) were treated with SAR443216. The median treatment duration was ~8 weeks in both 2-week and 3-week lead-in cohorts. Nearly all participants (97.5%) had at least one treatment-emergent adverse event (TEAE), of which 45% were grade ≥3. Most frequent TEAEs were cytokine release syndrome (CRS, 50%), fever (35%), alanine aminotransferase elevation (32.5%), aspartate aminotransferase elevation (27.5%), and infusion-related reactions (IRRs, 27.5%). No severe CRS, IRRs, fever, or pulmonary and cardiac toxicities were observed. Disease control rates were 34.5% in the 2-week and 36.4% in the 3-week lead-in cohorts. Average duration of disease stabilization was 10.48 weeks. Median follow-up time was 3.43 weeks. No objective responses were observed. The MTD was not reached. Dose-dependent PK showed overall consistent PK profiles across DLs. SAR443216 induced serum proinflammatory cytokines and increased multiple T-cell activation markers in peripheral blood mononuclear cells, indicating T-cell activation and target engagement. However, no clear trend in T-cell abundance or activation was observed among tumor-infiltrating T cells or other immune cells. These findings indicate that SAR443216 treatment is feasible and well tolerated in participants with R/R HER2+solid tumors. Further evaluation is warranted to fully characterize the efficacy and safety of SAR443216. NCT05013554.

Population ageing is reshaping cancer burden in later life. For stomach cancer, declining age-standardised mortality may coexist with sustained or increasing absolute deaths as older populations expand. We assessed stomach cancer burden among adults aged 65 years or older in aged and super-aged societies from 1990 to 2023. Using Global Burden of Disease Study 2023 estimates, we analysed deaths, disability-adjusted life-years (DALYs), age-standardised rates, age-specific mortality, sex-specific patterns, estimated annual percentage change, decomposition of changes in deaths, and trajectories around transition into super-aged status. Countries and territories were included if adults aged 65 years or older accounted for at least 14% of the population in 2023; super-aged societies were defined by a proportion of 21% or higher. Sixty countries and territories were included: 33 aged and 27 super-aged societies. In aged societies, deaths increased from 307,928 (95% UI 252,700-378,610) in 1990 to 336,454 (250,465-441,049) in 2023, despite a decline in the age-standardised death rate (ASDR) from 203.69 per 100,000 (166.46-251.77) to 90.12 (66.98-118.05). In super-aged societies, deaths decreased modestly from 105,330 (95,791-113,945) to 101,143 (81,472-116,462), while the ASDR declined from 162.13 (146.60-176.00) to 69.05 (57.17-78.77). ASDRs declined significantly in 59 of 60 countries and territories; Georgia showed a non-significant increase. Reductions were smaller at older ages, falling by 65% at ages 65-69 years but only 9% at ages 95 years or older. Decomposition showed that epidemiological improvements reduced deaths in nearly all countries, but population growth and ageing offset these gains in several settings, particularly China, Japan, and the Republic of Korea. Stomach cancer mortality rates declined substantially among adults aged 65 years or older, but absolute deaths declined less because demographic growth and ageing offset epidemiological gains, with burden increasingly concentrated at the oldest ages. Progress should therefore be assessed using both age-standardised rates and absolute burden.

Noninvasive differentiation of malignant and benign renal masses remains a major clinical challenge, particularly for radiologically indeterminate lesions. Here, we developed and validated a plasma cell-free DNA (cfDNA) fragmentomics-based machine learning classifier for renal mass characterization. The model was trained on 331 participants (171 cancer, 160 benign) and independently validated on 144 participants (73 cancer, 71 benign). Three cfDNA fragmentation features, including copy number variation (CNV), fragmentation-based methylation (FRAGMA), and nucleosome footprint (NF), derived from low-pass whole-genome sequencing, were integrated into an ensemble framework. The model achieved strong discriminative performance, with area under the curve (AUC) values of 0.956 in the training cohort and 0.946 in the validation cohort, outperforming individual feature-based models. At a predefined operating threshold corresponding to 90% sensitivity, specificity reached 0.90 and 0.87, respectively. Notably, most cancer samples exhibited low tumor fraction (TF < 3%), yet the model maintained robust performance in low-TF samples (AUCs: 0.952 and 0.941, respectively). Performance remained consistent across tumor stage, grade, and histological subtypes. The classifier also demonstrated potential clinical utility in diagnostically challenging settings, including lipid-poor angiomyolipoma and oncocytoma, with 12 of 13 oncocytoma samples correctly classified in an independent cohort. In addition, the model correctly identified 85.3% of benign masses > 4 cm, for which surgical intervention is more commonly considered, and 84.6% of malignant tumors ≤ 4 cm, for which management can be challenging. Collectively, these findings support cfDNA fragmentomics as a promising noninvasive liquid biopsy approach for renal mass evaluation and clinical decision-making.

Waldenström macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS) share the same cell of origin but differ in clonal size. Compared with other B-cell neoplasms, the lymphoplasmacytic clone in WM can be rather small, limiting our understanding of clonal expansion. We applied an integrative approach using single-cell RNA with B-cell receptor (BCR) sequencing, the assay for transposase-accessible chromatin, and whole-genome sequencing to characterize the tumor clone in patients with IgM MGUS, smoldering WM (SWM), and symptomatic WM (WM). IgM MGUS and low- or intermediate-risk SWM harbored multiple B-cell clones compared to WM. CD9, JCHAIN, RASSF6, and DUSP22 were the main markers of the dominant B-cell clone at gene expression and chromatin activity levels, with CD9 preferentially expressed in plasma cell-like tumor cells. POU2F2 had high activity in the tumor clone and was linked to CD9 regulatory regions. MYD88 and IGLL5 mutations, mainly associated with the mutational signature SBS5, were present in minor clones, whereas the MYD88 mutation was also detected in nonexpanded B-cells. The 6q deletion was present in tumor cells from high-risk patients, which harbored fitness advantage over copy-neutral tumor cells. Coding mutations clustered tumor and minor clones from oligoclonal patients and were associated with abnormal transcriptional programs. The B-cell clones also showed enriched predicted interactions with monocytes. Our integrative single-cell approach reveals the importance of clone size in IgM gammopathy and identifies key markers promoting clonal expansion.

Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment, yet the functional specialization of TAM subsets in metastatic progression remains incompletely defined. Here, we characterized distinct TAM populations contributing to tumor-promoting mesothelial cell conversion in high-grade ovarian carcinoma using single-cell RNA sequencing of patient-derived macrophages from ascites (ascTAMs) and omental metastases (omTAMs). TAMs from these anatomical sites were clearly distinguishable by polarization states, with omTAMs exhibiting a mixed M1⁺/M2⁺ phenotype, in contrast to the M1low/M2⁺ profile observed in ascTAMs. Transcriptomic analysis further revealed functional divergence of these subsets. Notably, omTAMs displayed gene signatures associated with mesothelial-to-mesenchymal transition (MMT), a critical process enabling tumor invasion across the peritoneal lining. Functionally, conditioned media from omTAMs, similar to that from classically activated M1 macrophages, induced MMT in primary mesothelial cells via TGFβ and ERK/p38 MAPK signaling pathways. This phenotypic transition enhanced transmesothelial tumor cell invasion. Proteomic analysis identified IL-1α as a key MMT-inducing factor secreted by pro-inflammatory macrophages. Mechanistically, IL-1α cooperates with TGFβ by activating an autocrine TGFβ/TGFBR1 feedback loop in mesothelial cells, thereby amplifying MMT. Consistent with these findings, IL1A expression was enriched in omTAM clusters across independent patient samples and was confirmed by immunohistochemical analysis of clinical samples. From a therapeutic perspective, our study identifies new avenues to counteract the mesothelial reprogramming driven by IL-1α⁺ TAMs, potentially impeding metastatic progression. Created in BioRender. Heidemann, S. (2026) https://BioRender.com/aeu6yd0 .

Galectin-3, a β-galactoside-binding lectin, is a driver and regulator of inflammation and fibrosis, and its levels are elevated in some heart and lung diseases. It also serves as a biomarker for the risk and severity of some forms of heart failure and, potentially, for various other pathological conditions. These observations make galectin-3 a promising potential therapeutic target. Both genetic and pharmacological inhibition of galectin-3 have been shown to ameliorate renal dysfunction and exert protective effects against liver fibrosis in animal models. Several galectin-3 inhibitors have been developed for therapeutic application in various pathological conditions. This review examines the progress of the development of 161 galectin-3 inhibitors, including monosaccharides, oligosaccharides, natural polysaccharides and their derivatives, carbohydrate polymers, antibody-drug conjugates, and non-carbohydrate compounds. Structure-activity relationships are emerging for these inhibitors, and the atypical binding pockets of galectin-3 have informed the development of a pharmacophore model that is expected to guide the design and discovery of potent, selective inhibitors for treatment of cancer, inflammation, and fibrosis.

T cell exhaustion has widespread implications for the progression and treatment of chronic diseases including tuberculosis, HIV, malaria, and cancer, yet current detection methods require expensive and tedious antibody labeling, destructive workflows, or days-long functional assays that limit dynamic monitoring capabilities. Here, we introduce Raman spectroscopy as a label-free assay for distinguishing T cell states directly from culture while preserving viability for downstream use. We leverage a 1-D convolutional neural network with sharpness aware minimization for machine learning-based spectral analysis, allowing us to identify critical Raman features for distinguishing exhausted T cells. We achieve >97% accuracy in discriminating unstimulated, activated, and exhausted T cells across three donors and multiple hardware setups, with >92% accuracy in identifying an intermediate activation-exhaustion transition state. We identify vibrational modes associated with alterations in nucleic acids and lipids as key features that distinguish T cell activation and exhaustion. In heterogeneous populations, we quantify exhaustion percentage with R2 = 1 and strong correlation to adenine (r = -0.91) and amide II protein (r = 0.94) vibrational modes. This work establishes vibrational fingerprinting as a direct measure of T cell exhaustion beyond surface marker expression toward scalable immune diagnostics, in-line monitoring, and selective immunopheresis.

Heat shock proteins (HSPs) are molecular chaperones that couple proteostasis to cancer metabolic reprogramming under oncogenic and microenvironmental stress. This Review integrates structural, biochemical, preclinical, and clinical evidence on HSP90, HSP70, HSP60, HSP40, HSP110, and small HSPs. We explain how ATPase cycles, chaperonin cages, co-chaperone networks, and organelle-specific localization stabilize metabolic enzymes, glucose transporters, hypoxia-responsive factors, and electron-transport-chain components, thereby coordinating glycolysis, mitochondrial bioenergetics, redox homeostasis, lipid metabolism, and metabolic plasticity. These mechanisms enable tumor survival and therapy resistance but also create context-dependent vulnerabilities. We critically evaluate pan-HSP and isoform-selective inhibitors, disruption of chaperone-client or co-chaperone interfaces, HSP-directed immunotherapies, and biomarker-guided combinations with metabolic or immune therapies. Clinical translation remains limited by systemic toxicity, compensatory heat-shock responses, tumor-type heterogeneity, and the absence of validated predictive biomarkers. We also assess circulating HSPs, cryo-EM analysis of chaperone complexes, and AI-assisted ligand design as routes for biomarker development and selective drug discovery. By linking chaperone architecture and client specificity to metabolic outputs and cancer phenotypes, this Review establishes a framework for differentiating actionable HSP dependencies from observational associations. It further defines priorities for patient stratification and precision oncology, supporting the development of selective and tractable strategies that target proteostasis-metabolism coupling.

L-lactate is generally elevated in tumors and acts as a signaling molecule that promotes tumor progression. Here, we reveal that malic enzyme 1 (ME1) functions as a previously unrecognized sensor of L-lactate through direct binding at arginine 155 (R155), thereby potentiating malignancy. Mechanistically, L-lactate binding promotes the nuclear translocation of ME1, a process involving reduced acetylation at lysine 362 (K362) and facilitated by nuclear import of karyopherin-α 4 (KPNA4). Nuclear accumulation of ME1 enhances metastatic potential, which is correlated with increased interaction with hepatoma-derived growth factor (HDGF) and acquisition of an epithelial‒mesenchymal transition (EMT)-related phenotype. Under nutrient-deficient conditions, L-lactate promotes the assembly of a ME1-lactate dehydrogenase B (LDHB) complex, which enhances oxidative phosphorylation (OXPHOS) and increases ATP production, suggesting a metabolic adaptive mechanism that supports tumor cell survival. Notably, the ME1R155A mutation, which disrupts L-lactate binding, abolishes the protumorigenic effect of the L-lactate-ME1 axis on tumor progression in vivo. In conclusion, our findings identify ME1 as a direct sensor of L-lactate and support a model in which lactate-mediated signaling and metabolic adaptation converge on ME1 to regulate tumor cell plasticity in a context-dependent manner under heterogeneous metabolic conditions. These insights advance our understanding of the spatiotemporal control of metabolic adaptation in cancer and reveal a potential therapeutic target.

Orally administered engineered probiotics, including Saccharomyces cerevisiae var. boulardii (Sb), are of emerging interest as protein therapeutic delivery platforms to treat gastrointestinal diseases. Tools to readily optimize protein output are required to optimize the therapeutic index of Sb-produced therapies. In this study, a 125-plex Sb secretion construct library was developed consisting of all possible combinations of five promoters, five secretion signals, and five terminators, which enabled a greater than 1800-fold range in Sb expression of a Gaussia luciferase (GLuc) reporter. Secretion signal and promoter identities had significant effects on secretion output. This library further enabled a 28-fold improvement of binding activity of Sb-secreted haPD-1, an established anti-tumor immunotherapeutic, and improved haPD-1 detection in mouse stool samples following oral gavage of Sb_haPD-1. Sb secretion trends of both GLuc and haPD-1 in vitro mirrored payload expression in vivo. This protein secretion library toolkit will serve as a valuable resource to rapidly optimize protein therapeutic output from engineered Sb.

Liver cancer exhibits profound spatial and cellular heterogeneity, contributing to tumour progression, invasion and therapeutic resistance. Emerging evidence suggests that rare low-abundance malignant cell populations residing within discrete tissue niches influence these processes. However, their reliable detection and identification remain challenging due to the limitations of conventional spatial and single-cell transcriptomic analyses, which often rely on single-sample convergence and a lack of cross-cohort reproducibility. To develop a robust framework for identifying rare malignant cell populations across heterogeneous spatial transcriptomic datasets and to characterise their functional role in liver cancer progression. We developed the Niche Cluster Atlas with Cellular Co-localisation (NCACC), a dual-layer framework integrating spatial organisation with cellular composition to enable cross-sample niche discovery. NCACC was applied to a comprehensive liver cancer transcriptomic atlas to identify rare niche-associated malignant cell populations. NCACC stratified liver cancer tumour architecture into reproducible multicellular niche modules and enabled a tumour-invasive front-enriched rare cancer-derived IgG (cIgG)+ epithelial cell population. These cells enhanced proliferative and invasive characteristics and were associated with disease progression. Mechanistic analyses identified a STAT1-dependent cIgG-JAK-STAT signalling axis sustaining the invasive-front phenotype and promoting cIgG+ epithelial cell aggressive behaviours. We then combined structure-guided virtual screening with patient-derived organoid validation to identify nordihydroguaiaretic acid and gallic aldehyde as candidate modulators. Our study establishes NCACC as a generalisable framework for high-confidence rare malignant cell identification across heterogeneous spatial transcriptomic cohorts, highlighting the cIgG-JAK-STAT as a therapeutically actionable driver of liver cancer invasion.

The clinical management of biliary obstruction has long relied on mechanical drainage provided by stents, yet the inherent risks of re-occlusion, infection, and migration underscore the fundamental limitations of this passive support paradigm. This review proposes a four-stage paradigm evolution framework for biliary stent technology, demonstrating a shift from "passive physical support" to an "active therapeutic platform." The first stage, represented by plastic and self-expandable metallic stents, established anatomical drainage but is limited by biofilm deposition, tumor ingrowth, and migration. The first paradigm shift introduced functionalized stents incorporating drug-eluting, radionuclide, or photothermal/photodynamic coatings, transforming stents into active therapeutic carriers. The second paradigm shift emphasizes bio-adaptation through fully biodegradable stents achieving "temporary support followed by disappearance," alongside cell/matrix coatings to promote tissue regeneration. A third paradigm shift is emerging, focusing on intelligent responsiveness and personalization through closed-loop systems integrating biosensors, wireless communication, and artificial intelligence for real-time monitoring and on-demand therapy, combined with 3D/4D printing for patient-specific adaptation. Through critical assessment of each stage, this review dissects translational challenges including evaluation standards, long-term safety, cost-effectiveness, and regulatory complexities. Ultimately, we present a clinical decision-oriented technological spectrum delineating stent positioning across benign and malignant biliary diseases, envisioning future dynamic platforms integrating diagnosis, treatment, and monitoring to advance biliary intervention into an era of data-driven precision therapy. STATEMENT OF SIGNIFICANCE: This review establishes, for the first time, a four-stage paradigm evolution framework for biliary stent technology-from passive mechanical support to active functionalized intervention, bio-adaptive scaffolds, and ultimately intelligent diagnostic-therapeutic platforms. By systematically dissecting the irreconcilable contradictions inherent to each paradigm, this framework provides a design-philosophy navigational map that transcends conventional chronological classifications. The integration of materials science mechanisms, cross-technology quantitative comparisons, and evidence-based clinical decision pathways offers both clinicians and biomaterials researchers a comprehensive reference for understanding the past trajectory and future direction of biliary stenting.

Nitric oxide (NO) and hydrogen peroxide (H2O2) are critical in redox homeostasis, cell signaling, and tumor progression, yet the simultaneous detection of both remains challenging due to their low concentrations and high reactivity. Herein, we developed an implantable, fully flexible electrochemical biosensor based on a Fe-porphyrin metal-organic framework (i.e., PCN-224(Fe)) for real-time monitoring of NO and H2O2 in complex biological environments. This platform employs PCN-224(Fe) with enzyme-mimicking activity as the catalytic material, combined with nitrogen and boron codoped graphene fiber as the freestanding and flexible microelectrode substrate. The resultant electrochemical sensor demonstrated outstanding performance, with detection limits of 3.0 nM for NO and 0.5 μM for H2O2, and sensitivities of 2.99 mA cm-2 mM-1 and 1.04 mA cm-2 mM-1, respectively. This performance surpasses most previously reported electrochemical sensors. The sensor also shows excellent selectivity and reproducibility, facilitating continuous monitoring of NO and H2O2 signals in the tumor microenvironment. The proposed fiber-based sensor enables in situ, real-time, continuous monitoring of NO and H2O2 in cancer cells, tissues, and living organisms, thereby effectively discriminating between cancerous and normal samples based on significantly elevated biomarker levels in malignant tissues. When implanted directly into living tissues, the sensing device captures dynamic biomarker fluctuations in vivo with high fidelity, offering a distinct advantage over traditional in vitro assays, which often introduce signal loss and concentration artifacts during sample processing. As a result, this approach provides a more accurate reflection of actual in vivo conditions and holds great promise for assessing tumor progression as well as monitoring therapeutic responses.

Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8+ T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

Conventional photothermal nanotheranostics suffer from fluorescence quenching caused by energy transfer between imaging and photothermal agents. Although unimolecular nanotheranostic systems circumvents the issue, it remains inadequate for generating substantial fluorescence and photothermal effects simultaneously under single-wavelength excitation. Herein, we develop a molecular aggregation engineering strategy by spectrally decoupling the monomeric state for fluorescence from the aggregated state for photothermal conversion within a unimolecular dye nanoplatform, enabling simultaneous theragnostic. We introduce a kinetic assembly method to encapsulate both NIR-II dyes (DQP) and protein in polymers, precisely regulating the aggregated state. Moreover, strong π-π stacking of the aggregated state of DQP drives photothermal effect, which functions as a thermal stimuli trigger for temperature-responsive DQPNPs to achieve charge reduction and size enlargement, promoting intracellular tumor retention, which ultimately improves fluorescence intensity and enhances photothermal efficacy. Such a molecular aggregation engineering strategy ensures precise tuning of the aggregated state of dyes, which realizes a breakthrough for balance NIR-II fluorescence with photothermal effect, supporting personalized and long-term cancer therapy.

Persistence of common ultraviolet (UV)-induced lesions, like cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4-PPs), typically results in C>T substitutions at dipyrimidines: a mutation pattern that composes the single-base substitution (SBS) signature 7 in cancer. Oncogenic melanoma mutations rarely involve SBS7-like substitutions. We recently identified noncanonical UV-induced mutations in yeast that appear to originate from atypical AC and TA photoproducts. While an AC photoproduct could account for formation of BRAF V600K, other melanoma drivers like BRAF V600E and NRAS Q61K involve other mutation types, suggesting possible existence of additional atypical photoproducts. Here, we couple temperature-induced telomeric end resection in yeast with serial UV irradiation and whole-genome sequencing to show UV light induces an extended array of noncanonical mutations in single-stranded DNA (ssDNA). This includes AT>AM, GT>GV, AC>AA, AT>TT, and TA>TT substitutions that are resistant to photo-reversion, indicating that they likely originate from atypical photoproducts. UV-induced mutation spectra in yeast lacking Rad30 indicated that Pol η plays substantial roles in the bypass of CPDs and 6-4-PPs regardless of telomere proximity. Unexpectedly, expression of a mutant DNA pol ε (pol2 M644G) reduced both canonical and noncanonical UV-induced mutations specifically within subtelomeric regions of the genome. This suggests a preferential role for pol ε in the resynthesis of uncapped telomeres, with the M644G mutation conferring accurate lesion bypass capabilities to the replicative polymerase. ssDNA-specific UV lesions provide additional damage-mediated mechanisms for the production of oncogenic mutations in melanoma, such as the BRAF V600E mutation that involves a GT>GA substitution.

Hepatocytes are highly specialized epithelial cells that maintain liver metabolic homeostasis, yet they also display remarkable plasticity in response to physiological demands, injury, disease, and oncogenic stress. In this review, we propose hepatocyte plasticity as an integrative framework that links homeostatic metabolic zonation, injury‑ and disease‑induced zonal remodeling and regeneration, hepatobiliary lineage conversion, and zonally biased malignant transformation. We first delineate homeostatic liver zonation as the baseline spatial architecture that constrains, rather than itself constitutes, hepatocyte plasticity, whereas dynamic re-zonation and state conversion represent plastic responses to perturbation. We further propose a conceptual framework that categorizes these plastic responses into four distinct yet interconnected modalities: transient adaptive state transitions, partial lineage conversion, transdifferentiation, and malignant lineage switching. We delineate the multiscale regulatory mechanisms underpinning each category, and critically assess the translational gaps between murine models and human disease. We further explore the therapeutic duality of this plasticity, evaluating emerging approaches that seek either to exploit its regenerative potential for liver repair and disease regression, or to counteract its pathological roles in cancer progression. By integrating these insights, this review establishes a comprehensive framework for understanding hepatocyte plasticity as a central determinant of liver pathobiology and highlights its translational potential for precision therapeutics in liver disease and cancer.

Mutations in the transcription factor LMX1B have been identified as the cause of the autosomal-dominant disease nail-patella syndrome. It manifests in small or absent patellae and dysplastic or missing toe- and fingernails, but the prognosis of the patients is determined by the development of renal symptoms due to dysfunctional podocytes. The pathogenetic mechanisms leading to podocyte damage and their association with specific mutations in the LMX1B gene are not understood, which has impeded the development of specific therapeutic strategies. Here we identify the pathogenetic mechanism affecting many patients with nail-patella syndrome, provide proof of principle for a novel therapeutic approach and suggest a domain-specific effect in gene regulation by LMX1B. Interestingly, missense mutations in the LIM domains of Lmx1b result in a recessive phenotype in two different knock-in mouse lines due to proteasomal degradation of the mutated proteins. The decreased half-life of the mutated LMX1B proteins can be attributed to ubiquitinylation and is prolonged by two proteasomal inhibitors, one of which was also tested in our mouse models and results in an alleviation of the renal symptoms. RNA sequencing of genetically altered podocytes indicates that LMX1B predominantly acts as a transcriptional repressor and furthermore suggests that the two LIM domains contribute to the distinct regulation of LMX1B target genes. We conclude that proteasomal inhibitors, drugs already approved for treatment of patients with multiple myeloma, warrant further studies to prevent renal failure in patients with nail-patella syndrome caused by mutations in the LIM domains. These studies should be designed to deliver the drug specifically to podocytes and to target specific ubiquitin ligases in order to limit side effects.

The insulin-like growth factor (IGF) signaling pathway plays a pivotal role in regulating a myriad of cellular and physiological processes, including cell proliferation, differentiation, and the maintenance of redox homeostasis. This review provides a comprehensive overview of the IGF/IGF receptor (IGFR) signaling axis, outlining its historical milestones and delineating its evolution from foundational discoveries to contemporary advancements. We elucidate the structural components of pathway, including ligands, receptors, and IGF-binding proteins, and discuss how multilevel regulation integrates upstream signals with downstream effectors such as the PI3K-AKT and MAPK/ERK pathways. Particular emphasis is placed on the crosstalk between IGF signaling and other pathways, including insulin, EGFR, PDGFR, VEGF, Wnt/β-catenin, JAK-STAT, and TGF-β/BMP in homeostasis and pathophysiological processes. We further discuss the role of IGF signaling in pathological process, highlighting insights from animal models and its implication in a wide range of human diseases, including cancer, cardiovascular diseases, neurodegenerative conditions, metabolic syndromes, skeletal abnormalities, and autoimmune and rare genetic disorders. Finally, we examine the therapeutic potential of targeting the IGF/IGFR axis, current clinical research advancements, FDA-approved pharmacological agents, and ongoing clinical trials. By incorporating historical insights with up-to-date scientific breakthroughs, our review underscores the need for systems-level and context-specific approaches to better understand IGF signaling dynamics, thus paving the way for the development of precision and personalized therapeutic strategies.

Glioblastoma (GBM) remains a formidable clinical challenge, characterized by invasive growth, therapeutic resistance, and dismal patient survival. We report the development of HITMAN (highly localized electric field-induced tumor therapy using magnetically actuated nanoantennas), a wireless bioelectric therapy that selectively eradicates GBM cells with cellular precision. Magnetically actuated nanoantennas convert low-frequency (≤200 kHz), deep-brain-penetrant magnetic fields into localized electric fields, thereby triggering protein unfolding, membrane disruption, and ER stress. In vitro, HITMAN demonstrated superior efficacy compared to temozolomide (TMZ), significantly decreasing viability in drug-resistant, patient-derived GBM cells by 52.2%, versus 10% with TMZ while sparing neurons and astrocytes. Mechanistically, HITMAN activated the unfolded protein response and autophagy pathways, suppressed cell cycle and adhesion genes, reduced Ki-67 expression, disrupted cytoskeletal architecture, and elevated p53 levels, underscoring a multifaceted antitumor mechanism. In orthotopic mouse models, HITMAN significantly inhibited tumor growth, extended median survival by more than 50%, and exhibited no systemic toxicity. Thus, HITMAN offers a minimally invasive, spatially precise, and clinically translatable therapy for GBM.

The frequent development of chemoresistance in cancer presents a major clinical challenge, yet the underlying causes of heterogeneous drug responses remain largely elusive. Here, we systematically assessed the cellular differentiation status of human breast cancer cells using single-cell atlases and identified a distinct population of immature basal-like cancer cells marked by BCL11B. Notably, higher levels of BCL11B+ cancer cells are significantly associated with early relapse in patients with breast cancer who received chemotherapy. Functioning as a central regulator, B-cell lymphoma/leukemia 11B (BCL11B) delineates an immature cell state that preferentially transitions to a drug-resistant persister state during treatment through multiple preexisting and adaptive drug resistance programs. The cytokine tumor necrosis factor-α (TNFα) is revealed as a natural inhibitor of BCL11B and can directly reverse the emergence of chemoresistant persister cells. Therefore, we identify BCL11B as an unappreciated predeterminant of drug response and a therapeutic target for a subset of patients with breast cancer at high risk of developing chemoresistance.

Connexins are classically defined as structural subunits of gap junction channels that mediate direct intercellular communication, and their dysregulation is a recognized feature of many cancers. Growing evidence suggests that connexins can influence cancer by regulating nuclear activity via both gap junction-mediated transfer of signaling molecules and channel-independent functions. However, much of the available evidence remains observational, and the mechanisms underlying these transcriptional effects are incompletely understood. More recent studies have begun to address this gap, including work showing that connexins can localize to the nucleus and directly influence gene expression. In this review, we examine current evidence that connexins regulate nuclear activity in cancer, addressing both tumor-promoting and tumor-suppressive functions. We discuss how gap junctional intercellular communication influences nuclear activity through the exchange of ions and signaling molecules and distinguish these effects from those mediated by connexin protein interactions, scaffold functions, and the nuclear or perinuclear localization of connexins or their truncated isoforms. We propose that connexins integrate intercellular communication with intracellular signaling to shape nuclear regulatory programs in a context-dependent manner, and we highlight the key challenges that must be addressed before these mechanisms can be fully understood and therapeutically targeted.

Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a pivotal adaptor molecule in the receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) signaling pathways, which are essential for osteoclastogenesis. In this study, we identified WD40 repeat-containing protein 23 (WDR23), also known as DDB1-CUL4 associated factor 11 (DCAF11), as a novel binding partner of TRAF6. Our findings demonstrate that WDR23/DCAF11 acts as a negative feedback regulator of RANK/RANKL-induced osteoclastogenesis by promoting the autophagy-dependent degradation of TRAF6. Notably, RANKL induced the upregulation of WDR23 expression during osteoclastogenesis. WDR23 physically interacted with the TRAF domain of TRAF6 via the WD40 repeat domains 1 and 2 of WDR23, resulting in reduced TRAF6 protein stability by its autophagy-dependent degradation during osteoclastogenesis. By modulating TRAF6 protein levels, WDR23 attenuated RANKL signaling cascades, including nuclear factor-κB and mitogen-activated protein kinases, thereby downregulating the expression of osteoclastogenic markers, such as nuclear factor of activated T-cell c1, tartrate-resistant acid phosphatase, dendritic cell-specific transmembrane protein, V-ATPase subunit d2 and cathepsin K. Conversely, WDR23 knockdown or deficiency enhanced RANKL-induced osteoclastogenesis by preventing the autophagy-dependent degradation of TRAF6. WDR23-deficient mice exhibit an osteoporotic bone phenotype characterized by elevated osteoclast formation and reduced bone mass. Collectively, these results establish WDR23 as a key negative feedback regulator of RANKL-induced osteoclastogenesis via autophagy-mediated TRAF6 degradation and underscore its potential as a therapeutic target for bone disorders associated with aberrant osteoclast formation and function.

SUMMARYThe messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccine platform is the newest tool in the vaccination arsenal for combating infectious diseases, rare genetic diseases, and cancer. Since 2020, major advances in preclinical and clinical studies have demonstrated the efficacy of mRNA-LNP vaccines against viral pathogens and in cancer. However, studies investigating the efficacy of mRNA-LNP vaccines against bacterial pathogens remain sparse due to substantial bacterial vaccine-specific challenges. Here, we highlight key challenges impeding the development of mRNA-LNP vaccines against human bacterial pathogens, the advantages that can be gained by utilizing the mRNA-LNP platform for bacterial vaccines, and progress toward the development of mRNA-LNP vaccines against bacterial infections.

Polycythemia vera (PV) is a clonal hematopoietic stem cell disorder resulting in overproduction of erythrocytes. Although interferon alfa (IFN-α) has shown therapeutic efficacy in PV and other myeloproliferative neoplasms (MPN), its precise mechanism of action remains poorly understood. In this study, we identify natural killer (NK) cells as primary immune effectors responsive to IFN-α treatment in PV essential for disease control in vivo. Using a transgenic mouse model of PV, we demonstrate that IFN-α induces the expansion of CD27+ NK cells in the bone marrow. In patients with PV or essential thrombocythemia undergoing IFN-α therapy, the frequency of CD56bright NK cells is increased and correlates with the molecular response. Depletion of NK cells abrogated the therapeutic effects of IFN-α. In vitro experiments demonstrate that NK cells preferentially killed Jak2VF mutant hematopoietic stem and progenitor cells in a tumor necrosis factor-α-dependent manner and independent of IFN-γ or NKG2D. Notably, PV mice depleted of NK cells or lacking type-I interferon receptor on NK cells showed accelerated disease progression in the absence of exogenous IFN-α. This suggests that direct sensing of basal levels of type-I interferons by NK cells is essential for attenuating disease progression, emphasizing a critical role for NK cells in immune surveillance of MPN. These findings offer new insights into type-I interferon-mediated immune modulation in MPN and highlight the potential of NK cell activation to improve therapeutic outcomes.

Driver mutations in T-cell acute lymphoblastic leukemia (T-ALL) rarely affect druggable kinases. However, these kinases can be aberrantly activated or repressed as secondary oncogenic events. Thus, integrating unbiased phosphoproteomics with genomic approaches may offer novel opportunities for target discovery and therapeutic interventions. In our study, we identified WNK1 (with no lysine [K]) as a potential target in T-ALL by pairing a list of vulnerable kinases with data from a phosphoproteomic screen of T-ALL cell lines. We subsequently validated WNK1 by loss-of-function-based studies and tested WNK inhibitors in several in vitro and in vivo T-ALL models and clinical T-ALL samples. We showed that therapeutic WNK1 repression promotes polyploidy, resulting in cell proliferation arrest, and morphometric changes, such as incomplete cell division or chromosome segregation through altered mitotic spindle assembly and abscission defects. Furthermore, we found that WNK1 is overexpressed in the TAL1/2-related subgroup, but not in normal thymus or lymph nodes, suggesting a potential translational area for clinical exploitation in poor-prognosis T-ALL carrying PTEN mutations and del(6q). Our work also reports a functional contribution of WNK1 in the leukemia establishment and progression. Structurally WNK1 is an atypical serine/threonine kinase that diverges from canonical kinases by lacking the conserved lysine in subdomain II, instead featuring a cysteine in subdomain I, which is critical for adenosine triphosphate (ATP) binding. This unusual structural configuration creates a distinct ATP-binding pocket with limited sequence similarity to conventional kinases, offering a unique opportunity to develop highly selective small molecules. Targeting this atypical ATP domain could thus provide a therapeutic advantage and broaden the treatment landscape for T-ALL.

Recurrent IDH-mutant gliomas frequently acquire increased radioresistance, leading to poorer outcomes. Their underlying mechanisms, however, remain largely unknown. We hypothesize that dysregulated RNA alternative splicing (AS) during IDH-mutant glioma recurrence contributes to the enhanced radioresistance by influencing critical cellular pathways. RNA sequencing of paired primary and recurrent IDH-mutant gliomas were analyzed to identify recurrence-associated AS events. Functional effects were assessed in patient-derived glioma stem cells using RNA interference and CRISPR-dCas13-mediated isoform switching. Candidate upstream RNA-binding proteins and antisense oligonucleotide (ASO)-based therapeutic strategies were evaluated in vitro and in vivo. We identified differentially spliced MutS homolog 5 (MSH5) isoforms between primary and recurrent IDH-mutant gliomas. Primary gliomas predominantly expressed an exon 11/12-skipped MSH5 transcript, whereas recurrent tumors largely retained the full-length isoform. Exon 11/12 skipping introduced a premature termination codon, leading to nonsense-mediated decay and diminished MSH5 expression in primary tumors. Further analyses identified elongation factor Tu GTP binding domain containing 2 (EFTUD2) as an upstream splicing regulator that was upregulated in recurrent tumors and promoted exon 11/12 inclusion, thereby maintaining MSH5 expression and enhancing the repair of radiation-induced DNA double-strand breaks. Inducing MSH5 exon 11/12 skipping with CRISPR-dCas13 or inhibiting EFTUD2 with ASOs reduced MSH5 expression, impaired DNA repair, and sensitized recurrent IDH-mutant glioma to radiotherapy in vitro and in vivo. These findings identify an EFTUD2-MSH5 splicing axis that contributes to radioresistance in recurrent IDH-mutant glioma. Therapeutic disruption of this splicing program may represent a strategy to enhance the radiation response in recurrent IDH-mutant glioma.

Cachexia is a debilitating muscle-wasting disorder associated with a high mortality rate in cancer patients. However, the molecular mechanisms of muscle contractile dysfunction underlying cancer-induced cachexia (CIC) remain poorly characterized. Here, we demonstrated that CIC reorients global SUMOylation in skeletal muscle cells and alters the stability of various SUMO machinery components, particularly SUMO isopeptidases. The non-canonical polycomb repressor protein L3mbtl2 was among the predominant proteins with enhanced SUMOylation level in CIC. Surprisingly, in contrast to previous notions, we found that L3mbtl2 activates transcription of a large cohort of genes regulating muscle contraction. Mechanistically, L3mbtl2 associates with Ash2L, a component of the SET1/MLL histone methyltransferase complex. Increased SUMO modification of L3mbtl2 in CIC leads to partitioning of Ash2L from its target genes, resulting in impaired calcium handling, sarcomere disorganization and impeded muscle cell contractile properties. Our findings reveal an unprecedented connection between SUMO and CIC, a paradoxical SUMO-associated transcriptional activator function of L3MBTL2 and hold potential for developing therapeutic interventions to ameliorate CIC.

Recent studies demonstrate that the gut mycobiota plays a key role in several tumors. However, the contribution of commensal fungi to prostate cancer initiation and progression remains understudied. Here we find that Nakaseomyces glabratus is enriched in fecal, blood and tumor samples of patients with castration-resistant prostate cancer, correlating with patients' poor overall survival. Oral administration of N. glabratus to castrated mice accelerated cancer progression by promoting infiltration and activation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, androgen deprivation therapy increases intestinal permeability, resulting in the leakage of N. glabratus from the gut to the tumor site, activating PMN-MDSCs via the Dectin-2 receptor. Treatment of mice with a negatively charged intestinal hydrogel blocks N. glabratus translocation to tumor, reducing PMN-MDSCs' intratumoral infiltration and activation. Taken together, these findings reveal that the gut-to-tumor translocation of N. glabratus contributes to endocrine resistance in prostate cancer by enhancing the immunosuppressive microenvironment of these tumors.

Drug discovery relies on cellular assays to determine whether a candidate produces a desired response, reveals its mechanism, or causes toxicity, but only a small fraction of compound-dose-time-context combinations can be measured experimentally. Recent perturbation atlases, single-cell and imaging technologies, and intervention-conditioned AI models now make prediction of unmeasured cellular responses a testable objective. AI virtual cells could therefore complement conventional discovery by prioritizing compounds, contexts, and follow-up experiments rather than replacing laboratory assays. Here, we review the resources and modeling advances supporting this capability, assess their value for mechanism-of-action analysis, efficacy, safety, resistance, and combination studies, and define evidence requirements for pharmacological use. Data coverage makes oncology, including immuno-oncology, plausible early proving grounds, with safety assessment as a crosscutting use case; broader deployment requires perturbation-specific, mechanistic, and decision-level validation.

GAIP-interacting protein C-terminal 1 (GIPC1/GIPC) is a well-established protein in the field of cancer biology. Recent studies have revealed that GIPC1 may exert opposing, context-dependent functions in various diseases or physiological processes, although the underlying regulatory mechanisms remain to be explored. Since GIPC1 contains a PDZ domain that interacts with various proteins, this domain is a promising therapeutic target. Molecular probes designed against the GIPC1-PDZ domain could therefore be valuable in developing targeted interventions. This review systematically summarizes the advances in GIPC1 research over the past decade. We discuss recent progress in understanding the roles of GIPC1 and its interacting proteins in human pathophysiology and disease, with a focus on GIPC1-interacting molecules and associated signaling pathways. Additionally, we identify key obstacles that must be overcome to realize the therapeutic potential of GIPC1. This review proposes an emerging conceptual model in which GIPC1 functions primarily as a context-dependent "signal tuner" and "trafficking gatekeeper," rather than as a simple scaffolding protein. This paradigm shift fundamentally transforms our understanding of how GIPC1 integrates diverse receptor inputs to regulate cellular behavior and highlights new directions for targeted therapeutic applications.

Type I collagen homotrimer is associated with age-related musculoskeletal, cardiovascular and fibrotic diseases - in addition to cancer - due to over-production of the alpha-1(I) chain from COL1A1, or inactivation of COL1A2. Type I collagen homotrimer in the osteogenesis imperfecta model oim does not cause bone fragility but exacerbates the oim phenotype. Here Col1a2 null and oim tail tendons were analysed to elucidate the role of collagen homotrimer in soft collagenous tissues. In Col1a2 null homozygotes, tendon diameter was reduced at 8 weeks old, whilst at 18 and 52 weeks old maximum modulus and hysteresis strain energy density were reduced and strain at maximum modulus was increased. Failure strain increased at 52 weeks. Oim homozygotes had additional changes in tendon diameter at 18 weeks, with narrower collagen fibrils and reduced hysteresis strain energy density at 8 weeks old, and reduced percentage hysteresis at both ages. There was evidence of type I collagen homotrimer in Col1a2 null heterozygotes, which had significant but less pronounced changes in failure strain, strain at maximum modulus and hysteresis strain energy at 18 weeks than homozygotes. Proteomics identified altered matrix protein composition in Col1a2 null and oim homozygotes whilst tissue fluorescence increased in Col1a2 null homozygotes at 52 weeks. Hence homotrimeric type I collagen affects the material properties and matrix protein composition of tail tendon following adolescence, whilst the oim mutation introduces earlier and additional alterations to energy dissipation. STATEMENT OF SIGNIFICANCE: Type I collagen is normally a heterotrimeric molecule but homotrimers can also be formed. To study how type I collagen homotrimer affects tissues, genetic inactivation of Col1a2 in mice was used to study the effect on tail tendon biomechanics and protein composition. Tendons comprising solely homotrimeric collagen displayed altered biomechanical properties that were more pronounced at older ages, indicative of damage accumulation or adaptive responses. An altered protein composition indicates both compensatory over-production and corresponding loss of other matrix proteins that may modulate tissue biomechanics. Findings in heterozygotes indicate that even partial homotrimer production is sufficient to alter tendon properties and provides insight into the tissue-level consequences of musculoskeletal and cardiovascular disease associated with type I collagen homotrimer production.

Predicting drug efficacy across diverse patient contexts remains a major challenge in oncology, as models trained on cancer cell lines often fail to capture patient-specific biology. Emerging biological foundation models and patient-derived technologies offer a promising solution. Here, we present UniCure, a multi-modal model that combines biological and chemical foundation models to predict drug-induced transcriptomic responses across diverse cell and tissue contexts, enabling individualized drug ranking. Trained on 1.9 million transcriptomic perturbation profiles spanning >22,000 compounds, 166 cell types, and 24 tissues, UniCure accurately predicts dose-dependent and combination responses and generalizes across bulk and single-cell data. We further fine-tune UniCure on 345 patient-derived tumor-like cluster (PTC) transcriptomic profiles and validate performance on 396 real-world clinical profiles, demonstrating effective patient-level prediction. The model supports response-based patient stratification and is experimentally validated in cell line and patient-derived models. Overall, UniCure provides a practical framework for translating preclinical data into personalized therapeutic strategies.

While obesity is generally associated with unfavorable health outcomes, there are notable exceptions. In cancer immunotherapy, epidemiological studies consistently link obesity to improved checkpoint inhibitor responses. Desharnais et al. show in mouse models that this paradox is driven by diet-dependent interactions with the gut microbiome, not obesity itself.

The mitochondrial E3 ligase MARCH5 has consistently emerged as a dependency in unbiased screens in acute myeloid leukemia and myeloma, yet the underpinning mechanism remains ill-defined. Here, we show that MARCH5 cooperates with UBE2J2 and MFN2, forming a stress-sensing complex at mitochondria-ER contact sites (MERCS) that restrains apoptosis in response to diverse organellar damage signals. Loss of MARCH5 potently sensitizes diverse blood cancer cell lines to BCL-2 and BCL-XL inhibition and compromises stress tolerance. By contrast, non-hematopoietic cell lines exhibit a phenotype largely restricted to BCL-XL dependence, permitting tissue-selective therapeutic synergy with venetoclax and other agents. Mechanistically, spatial organization underpins this specificity. The complex assembles at MERCS, where it co-localizes with BCL-2 and BCL-XL but not MCL-1. Upon organellar damage, it dissociates prior to BAX/BAK activation, lowering the apoptotic threshold and enforcing reliance on neighboring BCL-2 and BCL-XL. Consistent with its distribution, MARCH5 loss minimally alters MCL-1 dependence, revealing a spatially encoded mechanism integrating diverse stress signals into cell-death decisions. To guide future therapeutics, we demonstrate that disrupting key protein-protein interactions within this complex is sufficient to sensitize blood cancer cell lines, restoring venetoclax responsiveness and prolonging survival in a murine model of refractory lymphoma. Genetic deletion of MARCH5 or UBE2J2 restored BH3-mimetic sensitivity to primary chronic lymphocytic leukemia cells rendered resistant by cytokine stimulation. These findings establish the MERCS-resident MARCH5 complex as a central regulator of malignant cell stress tolerance and highlight tractable protein interfaces for therapeutic targeting.

The nuclear pore complex (NPC) and its building-block proteins, nucleoporins (NUP), play fundamental roles in maintaining cellular fitness by regulating nucleocytoplasmic transport, chromatin and transcriptional activity, and genome stability. These core biological processes are critical for cancer cells, and thus, tumor-driven co-option of NUP-regulated functions has emerged as an important mechanism contributing to the pathogenesis of multiple malignancies. This review discusses how NUP dysregulation mechanistically contributes to tumor initiation and progression and how these insights open opportunities for innovative anticancer therapies, including using clinical-grade molecular glues that induce selective NUP degradation and pharmacologically inhibiting NPC-regulated epigenomic/transcriptomic signaling and nucleocytoplasmic transport. Recent studies demonstrate that NUPs play fundamental roles in cancer pathogenesis by dysregulating key NPC functions and driving tumorigenesis and disease progression. NUPs and NPC-regulated mechanisms can be pharmacologically targeted, providing a strong rationale for developing much-needed innovative therapeutic strategies to combat cancer.

Fusions between protein-coding genes are common oncogenic drivers, typically pairing a proto-oncogene with a partner that does not independently drive cancer. In all therapeutically actionable fusions, the proto-oncogene is the drug target, the contributions to oncogenicity of the fusion partner have largely been ignored. We studied the role of BRAF fusion partners and found that they are necessary for transformation. In the setting of KIAA1549::BRAF, the most common fusion protein across brain tumors, we found that KIAA1549 is necessary for oncogenicity of KIAA1549::BRAF and engenders a striking and specific dependency on the protein O-mannosyltransferase complex (POMT1/2). Specifically, we show that genetic silencing or pharmacologic inhibition of POMT1/2 reverses fusion-induced transformation, thereby representing a novel and MAPK-independent therapeutic target. Furthermore, POMT1/2 is required to glycosylate and enable maturation of the K::B fusion protein. These findings represent a proof-of-concept for targeting the partners in oncogenic fusions as a potential cancer therapeutic strategy.

Extracellular vesicles (EVs) are membrane-bound, nano-sized particles released by diverse cell types. They serve as key mediators of intercellular communication by transporting a broad repertoire of proteins, lipids, nucleic acids, and metabolites to recipient cells within a protective lipid bilayer. Owing to their natural origin, intrinsic stability, low immunogenicity, and ability to cross biological barriers, EVs are highly attractive candidates for next-generation therapeutics and drug delivery platforms. In this review, we summarize the biology of EVs and highlight the features critical for their application in therapeutic delivery. We trace their multiple origins, ranging from mammalian and plant cells to bacteria, underscoring their ubiquity across biological systems. We then analyze the advantages of EVs as next-generation delivery vehicles. From a practical standpoint, we examine current strategies for EV isolation, purification, characterization, and engineering. Importantly, we showcase several therapeutic applications of EVs for intractable diseases that are refractory to conventional approaches, such as cancer and immune disorders. We also discuss the major challenges on the path to clinical translation, particularly scalable and standardized production, as well as safety and immunogenicity. To fully realize the clinical potential of EV-based therapies, future research should prioritize the development of robust manufacturing protocols and comprehensive safety evaluations.

Single-cell technologies have transformed our view of normal and malignant hematopoiesis, yet a framework linking lifelong homeostatic hematopoiesis to hematological diseases in blood ecosystem remains incomplete. Here, we constructed a high-resolution landscape of the entire hematopoietic system by integrating transcriptomes of ∼1 million cells from 207 healthy samples spanning five developmental stages (fetal, neonatal, childhood, adult, elderly), and identified 96 blood cell clusters, including a VNN2-marked monocyte subset in the fetus and TSHZ2-marked T cell subsets exhibiting distinct age-dependent dynamics. We uncovered a reversal in hematopoietic stem cell/multipotent progenitor (HSC/MPP) stemness around childhood and a postnatal lymphoid bias shift from reduced early B/T lineage potential to enhanced natural killer (NK) cytotoxicity, coordinately orchestrated by intracellular transcription factor activity and intercellular interactions. Projecting 116 pan-malignancy samples (9 hematological malignancies) to our refined blood cell reference, we identified the upregulation of MYC and MHC II signaling as relatively conserved features correlating with poor prognosis, while hematopoiesis-related modules exhibited subtype-specific distributions with divergent clinical implications. Importantly, we developed a prognostic framework incorporating two core signatures shared across hematological malignancies and subtype-specific features. We further revealed an antagonism between inflammatory and cytotoxic programs across malignancies. Together, we established a panoramic landscape of the human hematopoietic system and elaborated its lifelong behaviors, in which a steady-state reference enabled the delineation of pathological hallmarks across hematological malignancies.

Immunotherapies putatively require tumor-specific T cells. Here we show how T cells can eliminate tumors without tumor specificity via paracrine signaling. Activating unexhausted bystander non-tumor-specific T cells within tumors resulted in tumor elimination without conventional recognition-dependent mechanisms and in the absence of any tumor-specific T cell receptor (TCR)αβ+ T cells. Robust T cell activation recruited immune cells, used innate leukocytes and triggered a tumoricidal combination of effector molecules and panoptotic pathways. Mechanistically, interferon-γ, tumor necrosis factor and nitric oxide induced caspase-dependent death, recapitulating melanoma clearance in mice or human melanoma cell death in vitro. Gene expression signatures associated with this response in mice were predictive of survival among human patients with melanoma. Thus, triggering productive T cell activation within tumors can be sufficient for immunotherapy, without needing to induce or rescue cancer-specific responses.

A cell's proteome is assumed to reflect its transcriptional and translational activity. Macrophages regularly acquire xenobiotic material from neighboring cells, which is thought to result in degradation of the material. However, increasing lines of evidence suggest that not all taken up material is degraded and other transfer-like processes also occur. Field standard technologies are unable to rigorously report on precisely how and by whom the macrophage protein repertoire is altered during these interactions, leaving unresolved the extent to which nondegradative processes contribute to altered phenotypes. Here, we leveraged chemical tools and proteomics to show that intact target cancer cell surface proteins are transferred to the macrophage cell surface at functionally impactful levels in a manner associated with live-cell uptake. Widespread acquisition of proteins during cell uptake reengineers the macrophage cell surface proteome and is a transcriptionally silent, cell-nonautonomous process with the potential to alter metabolic uptake.

Despite the remarkable progress in cancer treatment, drug resistance and immune escape still severely limit clinical efficacy, largely due to tumor-induced immunosuppression. The main driver of this suppressive environment is myeloid-derived suppressor cells (MDSCs). Tumor-derived cytokines and chemokines can induce the expansion, activation, and recruitment of MDSCs, enabling them to effectively protect tumor cells from being recognized and cleared by immune cells by establishing an immunosuppressive barrier in peripheral lymphoid organs and the tumor microenvironment (TME). Upon arrival in the TME, MDSCs may alter their gene expression patterns through metabolic reprogramming, undergo skewed differentiation toward tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs), and initiate immunosuppression to promote tumor growth. Furthermore, they can shape an environment conducive to tumor development and metastasis through various nonimmune mechanisms. Currently, the overall understanding of the systematic integration of MDSC biological properties into therapeutic strategies remains underdeveloped. Therefore, in this review, we systematically summarize: (i) the classification and identification of MDSCs; (ii) their biological properties in the context of tumors and autoimmune diseases; (iii) tumor-promoting effects; (iv) genetic and signaling pathway regulatory mechanisms; (v) differentiation skewing in the TME; and (vi) cellular interactions with the TME. We also propose the clinical potential of MDSC-based predictive and prognostic biomarkers and outline strategies for targeting MDSCs for oncotherapy.

Receptor tyrosine kinases (RTKs) classically function as oncogenic drivers that promote survival and proliferation upon ligand binding. A subset of RTKs can also function as dependence receptors, inducing apoptosis in the absence of their ligands. Genetic alterations that enhance RTK signaling are well characterized in cancer and can be targeted with kinase inhibitors, which show limited efficacy in some clinical settings. Elucidation of whether oncogenic mutations can promote tumorigenesis by directly abolishing the pro-apoptotic activity of dependence receptors could help improve strategies to target RTKs. Here, we identified MET exon 14 skipping (METex14Del) as a paradigmatic example of an oncogenic alteration that drives tumorigenesis through genetic inactivation of the dependence receptor function of an RTK. METex14Del removed both the caspase cleavage site and adjacent CBL-binding motif, preventing generation of the pro-apoptotic p40MET fragment while sustaining oncogenic MET signaling. Uncoupling regulatory functions of MET using genome editing showed that loss of apoptosis capacity is a critical determinant of METex14Del-driven tumorigenesis. Combined-but not individual-mutation of the caspase and CBL sites was sufficient to recapitulate resistance to apoptosis and tumor growth induced by METex14Del in HGF-humanized mouse models. Importantly, inducible re-expression of p40MET in METex14Del-expressing cells restored apoptotic sensitivity, decreased tumor formation in vivo, and resensitized tumors to capmatinib. Together, these findings redefine RTKs as receptors with dual oncogenic and tumor-suppressive functions and show that disruption of dependence receptor-mediated apoptosis is an oncogenic mechanism. These results provide a conceptual framework explaining why therapies targeting only RTK signaling may fail and support strategies restoring dependence receptor function to achieve durable tumor suppression.

MXenes, a rapidly expanding family of two-dimensional transition-metal carbides, nitrides, and carbonitrides, have gained considerable attention as highly versatile nanomaterials for biomedical applications owing to their high electrical conductivity, chemically tunable surfaces, mixed ionic-electronic transport, and controllable redox activity. This review provides a structured overview of MXene-based biomedical technologies, organized by their functional interaction with the human body. We first examine on-body applications, highlighting MXene-enabled wearable, epidermal, and implantable bioelectronics. We then discuss in-body applications, including regenerative medicine, advanced cancer therapies, and antimicrobial strategies, emphasizing how MXene chemistry regulates biological interactions and therapeutic performance. Finally, we address applications outside the body, such as biosensing and diagnostic platforms, where MXenes enhance sensitivity, signal transduction, and imaging capabilities. Beyond summarizing recent advances, this review critically analyzes current gaps in knowledge, including long-term biocompatibility, degradation pathways, immune interactions, and structure-activity relationships, which currently limit clinical translation. We conclude by outlining key future directions, including sustainable synthesis, oxidation-resistant and fluorine-free MXenes, and the integration of artificial intelligence to accelerate materials discovery and application-specific design. Together, these insights position MXenes as chemistry-programmable nanoplatforms with strong potential to bridge on-body, in-body, and outside-the-body biomedical technologies.

Effective lung-targeted therapies can directly treat pulmonary diseases and engage tissue-resident immunity for lasting effects. However, protein delivery systems specifically targeting the lung remain scarce. Here, we report the discovery of phenylborate (PBA)-functionalized polymeric nanocapsules that enable efficient pulmonary delivery of protein cargos following systemic administration. Systematic structure-activity relationship studies revealed that PBA incorporation strongly correlates with enhanced lung tropism, establishing a previously unrecognized materials design principle for lung-targeted protein delivery. Leveraging this capability, we demonstrate that lung-targeted antigen delivery induces robust tissue-resident memory T cell responses within the pulmonary microenvironment and suppresses tumor growth in preclinical models of lung metastasis. Together, these findings redefine the in vivo functional role of phenylborate in nanocarrier systems and establish a versatile materials platform for lung-targeted protein therapeutics and site-specific immune modulation.

Single-stranded DNA (ssDNA) gaps represent an underappreciated vulnerability that directly shapes therapeutic response in BRCA-deficient models. Current clinical biomarkers remain anchored to the double-strand break (DSB) centric model of homologous recombination deficiency (HRD), and there are currently no tools available to detect replication-associated gaps in the clinical setting. Here, we developed a scalable, clinically adaptable assay that enables real-time, drug-free detection of gaps. This assay demonstrated that gaps are intrinsically elevated in BRCA-deficient cells independent of exogenous DNA damage. These gaps arose during DNA replication and were generated through PRIMPOL-dependent repriming at abasic sites and nuclease-mediated processing. Across diverse cell line models, PARP inhibitor (PARPi) sensitivity was associated with gap burden irrespective of BRCA status, extending the relevance of this vulnerability beyond canonical BRCA-mutant contexts. Integration with AI-driven image analysis enabled automated, unbiased quantification of gap levels in xenograft tumor specimens. In BRCA-deficient xenografts, elevated gap levels were associated with PARPi sensitivity, supporting their translational relevance in relation to therapeutic response. Together, these findings establish ssDNA gaps as a real-time functional readout associated with chemotherapy response and introduce an assay with potential for future clinical translation.

Effective T cell-based immunotherapies require functional receptors that can be engineered and redeployed to recognize tumor-restricted antigens. Noncanonical peptides arising from transcription outside annotated protein-coding regions expand the antigenic landscape of cancer; however, systematic strategies to biologically prioritize and functionally validate such targets remain underdeveloped. Here, we integrated de novo transcript analysis, exon-resolved quantification, RNA in situ hybridization, and immunopeptidomics to identify melanoma-associated noncanonical transcripts and advance candidates through receptor-level validation. Among three recurrent melanoma-associated transcripts, EVA003 emerged as a lead target based on its distinct repeat-enriched genomic architecture, consistent tumor-enriched exon-level expression across independent datasets, and a genomically unique immunogenic core sequence. We demonstrate endogenous presentation of EVA003-derived peptides on HLA-A*03:01 and detect specific reactivity in patient-derived tumor-infiltrating lymphocytes. Single-cell transcriptomic profiling identified a dominant peptide-reactive clonotype, enabling isolation of a naturally occurring T cell receptor. Transfer of this receptor into healthy donor T cells conferred antigen-dependent activation and cytotoxicity against both peptide-pulsed targets and melanoma cells expressing EVA003 endogenously. Together, these findings establish a biologically informed strategy for prioritizing noncanonical tumor antigens and demonstrate that genomically unique, tumor-enriched noncanonical peptides can be presented to molecularly defined receptors capable of mediating cancer cell killing. These findings support the integration of prioritized noncanonical antigens into engineered T cell therapeutic strategies.

Spatiotemporal monitoring of the dynamic extracellular microenvironment provides critical insights into tumor progression and drug metabolism. Conventional approaches typically collect overall metabolic information while ignoring spatial variations, limiting our understanding of the heterogeneous tumor microenvironment upon drug stimulation. To address this challenge, we developed a 3D SERS sensing platform by embedding plasmonic nanosensors into a biocompatible matrix within the tumor microenvironment. This platform enables spatiotemporal monitoring of H2O2 concentration and pH value through dynamic SERS mapping. The performance of this embedded sensing system was validated by evaluating the efficacy of a nanomotor-based drug carrier, which features a Janus structure with a platinum-catalyzed motor and doxorubicin-loaded exosomes. By tracking the dynamic spatial variation of the metabolic microenvironment, it was found that the active nanomotor not only extended the range of drug-induced oxidative stress from 45 to 70 μm and increased the concentration of deep-tumor H2O2 by 3-fold, but also alleviated deeper tumor acidosis compared to passive drug delivery. Consequently, the embedded SERS platform converts traditional average measurements into spatiotemporal tracking, serving as a promising analytical tool for assessing advanced drug nanocarriers beyond conventional endpoint or bulk assays.

DNA mismatch repair (MMR) maintains genomic stability, and defects in MMR genes such as MLH1 and MSH2 predispose to cancer. Unlike other MMR components, MLH1 has unexplained roles in development, as Mlh1-deficient male mice exhibit severe testicular hypoplasia and sterility. Here, we uncover that MLH1 regulates testis development through the Hippo-Yes-associated protein (YAP) pathway. MLH1 directly binds YAP via its C-terminal domain and the WW domains of YAP, competitively inhibiting LATS1-mediated YAP phosphorylation. This interaction stabilizes YAP by suppressing ubiquitination and promotes its nuclear translocation dependent on MLH1's nuclear localization signal. Additionally, MLH1 facilitates YAP-TEAD complex formation, enabling expression of testicular development genes, including Wt1, Sox9, and Ctgf. These functions are independent of the MMR activity of MLH1. Mlh1-deficient mice show elevated YAP phosphorylation, reduced target gene expression, and impaired proliferation in developing testes. Pharmacological inhibition of the Hippo pathway kinases MST1/2 partially rescues testis hypoplasia in Mlh1-/- mice. These findings establish MLH1 as a Hippo pathway regulator and resolve its long-standing role in male gonad development.

Venetoclax-based regimens have become increasingly integrated into the therapeutic landscape of acute myeloid leukemia (AML), yet primary resistance and relapses remain major barriers to durable benefits. Building on our previous discovery of CD84 as a critical survivor and redox regulator in AML, we here demonstrate that CD84 expression contributes to venetoclax sensitivity. Low CD84 expression is associated with favorable clinical response, whereas high CD84 expression correlates with primary resistance and is up-regulated at relapse in two of three paired samples. Functional perturbation of CD84 through genetic knockdown or CD84-targeted CAR-T cells sensitized AML cells to venetoclax in vitro and in vivo cell-derived xenograft models. Mechanistically, CD84 coordinates a pro-survival program with upregulating the antioxidant stress sensor SESN2, which suppresses mitochondrial reactive oxygen species and antagonizes venetoclax-induced apoptosis. SESN2 knockdown phenocopied CD84 depletion, while SESN2 overexpression partially restored venetoclax resistance in CD84-deficient cells. Our findings suggest that CD84-mediated upregulation of SESN2 contributes to venetoclax resistance and may represent a potential therapeutic target to enhance treatment efficacy in AML.

Over 20 years ago, it was established that the pro-inflammatory cytokine tumor necrosis factor-α (TNF) can directly regulate neurotransmitter receptor trafficking. On pyramidal neurons, TNF signaling results in the synaptic insertion of AMPA receptors and the removal of GABAA receptors, shifting the excitatory/inhibitory balance to a more excitable state. The glial release of TNF mediates homeostatic synaptic plasticity (HSP), a compensatory form of plasticity in response to chronic decreases in neuronal activity. This adaptive response can stabilize neuronal circuits, which may be beneficial during development and in certain psychiatric conditions. However, the homeostatic set-point may be dynamically regulated, in a process akin to allostasis. Under these conditions, TNF may act to create or maintain the altered circuit function underlying psychiatric disorders and disease states.

Metabolic remodelling underlies tumour progression. However, how metabolites act as signalling molecules to support cancer cell proliferation remains unclear. Here we show that argininosuccinate (ASA), a key intermediate of the urea cycle, promotes purine nucleoside biosynthesis in tyrosine kinase-driven haematological malignancies. Mechanistically, BCR-ABL phosphorylates argininosuccinate synthase 1 (ASS1), which increases ASA production from citrulline. ASA directly binds cytosolic 5'-nucleotidase II (NT5C2) and enhances its nucleosidase activity. The resulting purine nucleosides serve as a carbon source for glycolysis and the tricarboxylic acid cycle, which supports leukaemia cell proliferation under glucose-replete conditions. Loss of ASS1 or NT5C2 disrupts central carbon metabolism and inhibits leukaemia progression in vivo, which can be rescued with inosine or adenosine supplementation. Collectively, our findings uncover an ASA-NT5C2 signalling axis linking urea cycle dysregulation to purine metabolism, and identify purine nucleosides as a carbon source in tyrosine kinase-driven haematological malignancies.

The role of adaptive mRNA structures in regulating gene expression in mammalian cells remains poorly understood. Synonymous mutations have been linked to a range of diseases, including cancer, yet their impact on cell biology remains largely unexplored. This opinion focuses on how cancer-associated synonymous mutations (CASMs) in the TP53 mRNA disrupt signal-induced mRNA structures and alter the activity of the encoded protein. CASM203 induces conformational changes that recapitulate those driven by PERK during the unfolded protein response, promoting expression of the p53/p47 isoform. By contrast, CASM22 and CASM34 interfere with DNA damage-induced RNA structures and affect full-length p53 activity. Together, these examples illustrate an underappreciated regulatory axis in which dynamic mRNA structures interface between upstream signalling pathways and downstream effector functions, with direct implications for tumour biology.

Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood. To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC. We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens. TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8+ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8+ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis. Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

Neuronal activity is known to promote glioma growth, yet whether inhibitory circuits can oppose this effect has remained unclear. Here, we show that adult gliomas receive functional γ-aminobutyric acid (GABAergic) synaptic input from local inhibitory interneurons and that this input acts as a tumor-suppressive circuit signal. Enhancing inhibitory tone, genetically or pharmacologically, restrains tumor proliferation and prolongs survival, whereas disrupting inhibitory synaptic output accelerates tumor growth. Mechanistically, inhibitory circuit activation suppresses tumor calcium dynamics, and calcium gain- and loss-of-function experiments establish these dynamics as causal regulators of proliferation and survival. Yes-associated protein 1 (YAP1) and mechanistic target of rapamycin (mTOR) emerge as calcium-coupled oncogenic programs attenuated by inhibitory activation. Thus, adult glioma progression is governed not simply by neuronal activity but by a balance between growth-promoting and growth-restraining circuit influences. These findings define inhibitory input as a suppressive component of the glioma ecosystem and suggest that strengthening inhibitory tone may offer a therapeutic strategy.

A20, encoded by tumor necrosis factor alpha-induced protein 3 (TNFAIP3), is a ubiquitin-editing enzyme that acts as a central regulator of inflammatory signal termination, immune homeostasis and tissue protection. By controlling receptor-proximal ubiquitin signaling, A20 limits the amplitude and duration of inflammatory responses and thereby restrains the transition from acute host defense to chronic tissue-damaging inflammation. Genetic, biochemical and disease-model studies have linked altered A20 expression or function to a broad spectrum of human disorders, including monogenic autoinflammation, autoimmunity, barrier and fibrotic diseases, infection and cancer. However, the literature remains fragmented across organ systems and recurrent signaling pathways, obscuring the conserved biological functions of A20 and the contexts in which these functions become pathogenic. Here, we examine the mechanisms governing A20 activation, recruitment and ubiquitin-editing logic, with emphasis on the distinct contributions of the ovarian tumor (OTU) domain and zinc-finger (ZnF) modules. The major biological functions of A20 are then organized into recurrent output modules, including immune-cell homeostasis, signal termination, coordination of cell-death programmes, and oxidative-stress or immunometabolic adaptation. Disease associations are discussed according to dominant pathological outputs and vulnerable cellular compartments rather than by repetitive pathway listing. Finally, the therapeutic implications of A20 are assessed, including its potential as a biomarker and context-dependent therapeutic node, together with the translational challenges posed by cell-type specificity, disease-stage dependence and immune risk. A20 emerges as a context-dependent regulator of inflammation, tissue remodeling and tumour progression with relevance for biomarker development and precision therapeutic targeting.

Molecular glue degraders are an emerging class of small molecule allosteric modulators that induce or stabilize protein-protein interactions, enabling targeted degradation of previously intractable proteins. By redirecting E3 ligases to recognize neosubstrates, proteins that are not typically recognized by a specific E3 ubiquitin ligase, they expand the scope of drug discovery beyond traditional paradigms. We review mechanistic principles underlying molecular glue activity, including cooperativity, weak affinity interactions, structural degrons, and higher-order complex formation. We discuss discovery strategies, from serendipitous identification to emerging rational and chemoproteomic approaches, and key E3 ligase systems with relevance to oncology. We highlight clinical and preclinical applications, alongside challenges such as resistance mechanisms, context-dependent activity, and limitations in predicting neosubstrates. Molecular glues are transitioning from serendipitous discoveries to a mechanism-driven therapeutic platform. Progress depends on integrating structural biology, proteomics, and computational modeling to enable rational design and improve predictability. Expanding the repertoire of E3 ligases and understanding context-specific degradation will be critical to fully realize their potential in oncology and beyond.

Lipid modifications are critical for membrane anchoring and signal transduction. N-myristoylation, catalyzed by NMT1/2, irreversibly attaches myristic acid to N-terminal glycine residues, enabling stable membrane localization and crosstalk with other post-translational modifications. This review traces NMT research from structural characterization to substrate profiling, highlighting the ordered double-substitution catalytic mechanism and variations in substrate recognition. While prior reviews have covered NMT biochemistry and innate immunity, we emphasize underappreciated roles of N-myristoylation in metabolic vulnerability, immune evasion, and acquired resistance to targeted therapies and immunotherapies. We discuss how exogenous myristic acid from dietary sources fuels oncogenic signaling, and how N-myristoylation regulates key signaling pathways (PI3K/AKT, MAPK, ferroptosis) and targets (Src, AMPK, EZH2) to drive immunosuppressive and pro-tumor phenotypes. Antitumor potential of NMT inhibitors (e.g., B-13, Zelenirstat) and allosteric ABL1 inhibitors (asciminib) is evaluated. Recent methodological advances (including metabolic labeling, click chemistry, spatial proteomics, and computational simulations) are reviewed. However, translational challenges such as biomarker absence, blood-brain barrier limitations, and functional redundancy remain. Addressing these will require combination therapies tailored to specific mutational, metabolic, and immune profiles. In summary, N-myristoylation integrates signaling, metabolism, and immunity, offering a rationale for future precision oncology.

Preclinical research in cancer therapy-related cardiovascular toxicity (CTR-CVT) is a major domain of cardio-oncology and has provided biological explanation for the cardiovascular adverse effects of many cancer therapies. However, the choice of the experimental models to investigate the mechanisms of CTR-CVT is often based on personal experience and opinion, rather than on established principles and available evidence. Moreover, presentation of methods and results is frequently approximate. This Scientific Statement outlines potential quality standards regarding methodology and reporting in preclinical cardio-oncology research, with the goal of promoting accurate, reliable, and reproducible studies. Quality standards are distinguished in first-tier, when considered essential for robustness unless there is a strong justification for their omission, and second-tier standards, when desirable, but not necessary. First-tier standards ensure credible, self-sustaining research, while second-tier ones enhance quality of investigations and accelerate understanding of CTR-CVT. Adherence to the proposed quality standards is expected to benefit researchers embarking on new investigations, facilitate funding allocation, and inform the development of novel oncological therapies, eventually moving cardio-oncology science forward.

Carbamoyl phosphate synthetase 1 (CPS1) is primarily expressed in hepatocytes as a highly abundant mitochondrial matrix enzyme that catalyses the first step of the urea cycle that leads to renal nitrogen disposal. CPS1 is a member of the CPS family that manifests broad evolutionary expression from bacteria to humans. CPS1 expression and enzyme activity are highly regulated transcriptionally and post-translationally. Its autosomal recessive mutation leads to CPS1 deficiency, which causes encephalopathy and coma, typically neonatally, due to severe hyperammonaemia. CPS1 is physiologically secreted, apically, into bile likely via mitochondria-derived vesicles. Normally absent from serum, it is released by basolateral mistargeting and cellular injury and becomes readily detectable in serum during acute liver failure (ALF). Injury-triggered CPS1 release into blood, or media in cultured hepatocytes, is selective as compared with other mitochondrial proteins. This, coupled with its abundance and short (1-2 hours) serum half-life, renders it a prognostic serum biomarker, particularly in human acetaminophen-related ALF. Its rapid turnover is explained by its non-enzymatic role as an immune modulator via its uptake by circulating monocytes leading to differentiation of anti-inflammatory cells that home to, and protect, the injured liver. CPS1 also plays a growing role in several cancers, by CPS1 upregulation or downregulation, particularly via metabolic reprogramming which alters the tumour microenvironment and impacts cancer growth and progression. Therefore, CPS1 has multiple enzymatic and non-enzymatic touch points spanning a wide range of cellular and extracellular functions and roles, with important physiological, homoeostatic, genetic disease, diagnostic and potential therapeutic clinical implications.

Ergothioneine (EGT) is a diet-derived sulfur-containing histidine derivative with antioxidant, anti-inflammatory, and cytoprotective properties. In humans, its absorption, tissue distribution, and long-term retention are mainly mediated by the organic cation transporter OCTN1, which may help explain its accumulation in metabolically active and stress-prone tissues. Increasing experimental and clinical evidence links EGT to neurodegenerative, cardiovascular, metabolic, inflammatory, and age-related disorders, although its therapeutic value still requires confirmation in larger and longer-term clinical studies. This review summarizes the physiological functions of EGT, its OCTN1-dependent transport and tissue distribution, and the molecular mechanisms by which it may modulate oxidative stress, inflammation, mitochondrial function, and cellular senescence. Particular attention is given to the dual role of the OCTN1/EGT axis in aging and tumor biology. In addition, we briefly discuss current biosynthetic and biomanufacturing strategies as practical tools for obtaining high-purity EGT for mechanistic, preclinical, and translational studies. By placing production strategies in the context of biomedical research needs, this review aims to provide a medically oriented overview of EGT biology and its potential translational applications.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Tertiary lymphoid structures (TLS) have emerged as key components of the tumor immune microenvironment, associated with improved survival and enhanced immunotherapy response. However, non-invasive detection of TLS remains a significant clinical challenge. This multicenter study aimed to develop and validate a deep learning-based CT model to noninvasively predict TLS status and evaluate its prognostic and predictive value across surgical, non-surgical, and prospective immunochemotherapy cohorts. We enrolled 223 surgically resected patients with PDAC from two centers for model development and 82 non-surgical patients for clinical validation. A ResNet50-based deep learning network (DLN) was trained to predict TLS status from preoperative contrast-enhanced CT. The locked model was evaluated in 44 patients from a prospective immunochemotherapy trial (ChiCTR2000032293), with pathology-anchored verification, outcome assessment, and spatial immune profiling via cyclic multiplex tyramide signal amplification. The DLN achieved area under the curves (AUCs) of 0.987, 0.937, and 0.853 in training, internal, and external validation cohorts. In the non-surgical cohort (n=82), DLN-predicted TLS-positive patients had significantly longer overall survival (OS; median 19 vs 7 months; HR=3.611, p<0.0001). In the prospective cohort, pathology-anchored verification yielded an AUC of 0.929 (specificity=1.000). DLN-high patients demonstrated superior objective response rate (90.0% vs 26.5%, p=0.001), progression-free survival (PFS) (median 13.1 vs 5.3 months, p<0.001), and OS (median 17.6 vs 8.7 months, p<0.001). The DLN score independently predicted OS (HR=0.052, p<0.001) and PFS (HR=0.079, p<0.001) in multivariable analysis. The DLN score was orthogonal to programmed death-ligand 1 (PD-L1) expression (rho=0.011, p=0.946) but correlated with dendritic cell-T helper cell spatial interactions (p=0.037) and T helper-B cell spatial co-localization (rho=0.307, p=0.043)-two hallmarks of functional TLS architecture-and inversely with tumor cell density (rho=-0.399, p=0.007). This DLN-based CT model reliably predicts TLS status in PDAC with prospectively validated prognostic and predictive value in immunochemotherapy, biological grounding in TLS-associated spatial immune architecture, and orthogonal predictive value to PD-L1, supporting a complementary biomarker strategy for immunotherapy patient selection.

While immune checkpoint inhibitor-based neoadjuvant therapy shows promise in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), the optimal regimen has yet to be established. We report, for the first time, a neoadjuvant treatment that combines chemotherapy with dual blockade of the programmed cell death protein 1 and epidermal growth factor receptor pathways in LA-HNSCC. In this single-arm phase 2 trial (NCT05516589) conducted at a single academic center, patients with LA-HNSCC were enrolled and received two cycles of tislelizumab and TP chemotherapy (nab-paclitaxel and cisplatin), administered on day 1 of each 3-week cycle, along with afatinib during the interval between chemoimmunotherapy cycles, followed by surgical resection. The primary endpoint was the complete pathologic response (pCR) rate. Secondary endpoints included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival, overall survival (OS), and safety. A total of 40 patients were enrolled and received neoadjuvant treatment, 32 of whom proceeded to surgical resection; among these patients, the pCR rate was 40.6% (95% CI 23.7% to 59.4%). The ORR was 82.5% (95% CI 67.2% to 92.7%). The 1-year OS rate was 97.3% (95% CI 92.2% to 100%). The most common treatment-related adverse event (TRAE) of grade 3-4 was lymphopenia (5/40, 12.5%). No grade 5 TRAEs leading to death occurred, and no treatment-related surgical delays were observed. In the prespecified exploratory biomarker analysis, increased cytotoxic T lymphocytes and B cells in the tumor immune microenvironment may be associated with pCR/MPR. Neoadjuvant treatment induced a significant increase in the proportion of peripheral CD8+T cells, along with a reduction in B cells. We report, for the first time, the promising efficacy and acceptable safety profile of neoadjuvant chemoimmunotherapy combined with afatinib in patients with LA-HNSCC. Neoadjuvant treatment potentially induced an immune-enhanced tumor microenvironment. Further evaluation in large-scale clinical trials with longer follow-up periods is needed. NCT05516589.

Small cell lung cancer (SCLC) is a highly malignant tumor characterized by strong invasiveness and poor prognosis. Immune checkpoint inhibitors have provided new therapeutic options for SCLC, but their comparative clinical benefit remains unclear. This retrospective study enrolled 171 patients with SCLC treated between January 2016 and June 2023, with follow-up through June 30, 2024, to compare survival and safety profiles between anti-programmed death-1 (anti-PD-1) and anti-programmed death-ligand 1 (anti-PD-L1) inhibitors. Among the 119 patients (69.6%) who received immunotherapy plus chemoradiotherapy, the median overall survival (OS) was 48.3 months, compared with 25.2 months in those who did not receive radiotherapy. Multivariable Cox regression confirmed that liver metastasis and radiotherapy status were independently associated with OS and progression-free survival (PFS). Subgroup analyses revealed that patients younger than 65 years who underwent radiotherapy, particularly those without liver metastasis, achieved longer OS with anti-PD-1 agents. In conclusion, both anti-PD-1 and anti-PD-L1 inhibitors improved the prognosis of SCLC. Patients younger than 65 years receiving radiotherapy and those with limited-stage SCLC may represent populations more likely to benefit from anti-PD-1 therapy.

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy with limited therapeutic options. The spatial architecture and functional diversity of tertiary lymphoid structures (TLSs) in iCCA remain unclear. Here, we present a multimodal spatial atlas of TLSs and identified intratumoral TLSs (iTLSs) as independent prognostic markers. Bulk proteomic profiling of 214 discovery and 155 validation cases identified a four-tier TLS-based tumor microenvironment classification system and supported development of a TLS-predictive random forest classifier. Imaging mass cytometry revealed that iTLS+ tumors harbor structured immune architectures, where M1-like tissue-resident macrophages (RTMs), dendritic cells, and CXCL13+ CD4+ T cells colocalize to form antigen-presenting neighborhoods (apc-CNs) spatially coupled to TLS core regions (TLScore-CNs). Single-cell spatial transcriptomics further resolved 61 TLSs into 14 spatial niches and defined a pseudotemporal maturation continuum: aggregated, activated, and postactivated. Intraniche communication, primarily mediated by ifnCAFs, iCAFs, and CXCL12+ macrophages, evolved dynamically with maturation. Single-nucleus RNA sequencing combined with Tangram-based spatial mapping revealed CXCL12+ macrophages and iCAFs forming a peripheral band in aggregated TLSs, whereas ifnCAFs infiltrated TLS interiors during activation. These findings define TLS heterogeneity and provide insights for stroma-directed immunotherapy.

Experimental data suggest that COVID-19 vaccination could modulate immune checkpoint inhibitor (ICI) effects, but population evidence is limited. Using the French health data system (Système National des Données de Santé), we identified 95,015 adults initiating ICI therapy between December 2020 and March 2023. We assessed mRNA vaccination within 100 days before ICI initiation using inverse probability of treatment weighting and within 100 days after ICI initiation among previously unvaccinated patients using a cloning-censoring-weighting target-trial emulation. The primary outcome was all-cause mortality; secondary outcomes were cancer-specific and non-COVID-19 mortality. Follow-up extended to 31 December 2024 for all-cause mortality and to 31 December 2023 for cause-specific deaths. Pre-ICI mRNA vaccination was associated with lower early all-cause mortality (hazard ratio (HR) 0.90 (95% confidence interval (CI) 0.87-0.94) at 1-3 months and 0.96 (0.93-1.00) at 6 months) and no significant association after 12 months. Post-ICI mRNA vaccination showed a similar early association (HR 0.84 (95% CI 0.80-0.88) at 3 months and 0.86 (0.79-0.94) at 6 months), also with no significant association after 12 months. Estimates for non-COVID-19 and cancer-specific mortality were similar to those for overall survival. Similar early patterns with non-mRNA COVID-19 and other adult vaccines suggest modest, transient associations or healthy-vaccinee effects, rather than a specific mRNA COVID-19 vaccine effect.

The success of immunotherapies such as immune checkpoint blockade and engineered T-cells has demonstrated the immune system's anticancer potential. Although prophylactic vaccines against oncogenic viruses such as human papillomavirus prevent cancer by blocking infection, therapeutic vaccines targeting tumour-associated or tumour-specific antigens (TAAs/TSAs) have not reliably produced meaningful tumour regressions. Advances in DNA sequencing and computational pipelines for predicting individual, MHC-restricted neoantigens now enable personalized cancer vaccines (PCVs). By targeting neoantigens arising from somatic mutations, PCVs escape the central tolerance that limits anti-TAA vaccines. Multiple clinical trials have shown promise, but PCV design, delivery, and optimal disease settings require further refinement.

Histopathology is essential for cancer diagnosis and treatment selection, and pathology foundation models learn visual representations from whole-slide images (WSIs). However, existing foundation models are trained on disparate datasets with varying strategies, leading to inconsistent performance and limited generalizability. Here, we introduce ELF (Ensemble Learning of Foundation models), which integrates five pretrained pathology foundation models into unified slide-level representations. Trained on 53,699 WSIs spanning 20 anatomical sites, ELF leverages ensemble learning to capture complementary information across models. ELF's slide-level architecture is designed for data-efficient downstream evaluation, including settings with limited data such as therapeutic response prediction. We evaluate ELF for disease classification and biomarker detection, as well as anticancer and immunotherapy response prediction across multiple cancer types. ELF achieves higher performance than the evaluated constituent and slide-level foundation models across the tested tasks, supporting further evaluation of ensemble learning for pathology applications in oncology.

Patients with localized mismatch repair deficient (dMMR)/microsatellite instability (MSI)-high esophagogastric adenocarcinomas are rare and derive limited benefit from standard perioperative chemotherapy. Immune checkpoint inhibitors have demonstrated efficacy in metastatic dMMR/MSI tumors, and recent phase II studies have shown promising activity in localized stages. The multicenter, phase II trial IMHOTEP (NCT04795661) assessed perioperative pembrolizumab in nonmetastatic dMMR/MSI solid tumors. The esophagogastric cohort included patients with localized (cT2-4N0/N+M0) esophagogastric cancer and confirmed dMMR/MSI status. Patients received one or two infusions of neoadjuvant pembrolizumab (400 mg every 6 weeks) and optional post-operative pembrolizumab for up to nine cycles and were candidates for surgery. The primary endpoint was pathological complete response (pCR; ypT0N0). Between May 2021 and February 2025, among the 41 patients treated with pembrolizumab, 36 received one to two neoadjuvant pembrolizumab infusions and were eligible for surgery and included in the efficacy analysis (surgery: N = 27; no surgery: N = 9). Of note, five patients were excluded from efficacy analysis (inclusion/exclusion criteria not met, N = 3; >2 neoadjuvant pembrolizumab: N = 2). The subgroup of operated patients had R0 resection (N = 27), and four (14.8%) achieved pCR. With a median follow-up of 25.8 months, 25 (93%) patients experienced no progression, recurrence, or death. Grade ≥3 treatment-related adverse events occurred in nine (22%) patients. Perioperative pembrolizumab is feasible and safe in localized dMMR/MSI esophagogastric cancers. Further investigation is warranted to optimize the duration and nature of neoadjuvant immunotherapy.

Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR)MCC1, a highly avid, HLA-A*02:01-restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen15-23. Seven patients with ICI-refractory metastatic MCPyV+ MCC received TCRMCC1-transduced cells (TTCR-MCC1 cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). TTCR-MCC1 cells trafficked to tumor sites and expressed a gene expression profile compatible with T cell activation, with tumor regression observed in two patients. However, therapeutic activity was limited by HLA class I silencing, a common mechanism of immune escape in MCC. In one patient, delayed tumor regression coincided with endogenous effector immune activation and restoration of MCC HLA expression, implying that robust local responses could reverse HLA silencing. To overcome this barrier, we engineered CD4 and CD8 TTCR-MCC1 cells to coexpress CD8αβ and a CD200R-CD28 switch receptor, enabling CD4 T cell engagement and T cell costimulation. These modifications enhanced tumor infiltration, increased HLA expression, and improved control of HLAlow MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV+ MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.

Immune checkpoint inhibitors (ICIs) have transformed cancer outcomes but may be associated with an increased risk of myocardial infarction and ischemic stroke. Whether this risk is mediated by inflammatory plaque activation and whether coadministered vascular endothelial growth factor inhibitors (VEGFIs) modify the effect remain unresolved. To prospectively characterize the arterial and systemic inflammatory outcomes associated with ICIs, VEGFIs, and combined ICIs plus VEGFIs in patients with cancer. This prospective longitudinal cohort study was conducted between August 2022 and June 2024 at the West of Scotland regional cancer hospital network. Adults with cancer who were planned to receive ICI monotherapy, VEGFI monotherapy, or combined ICI plus VEGFI therapy underwent imaging and venous blood sampling at baseline (before treatment) and at 24 weeks. Data were analyzed from June 2024 to October 2025. Undergoing (18F)fluorodeoxyglucose positron emission tomography computed tomography ([18F]FDG-PET/CT) imaging. Arterial inflammation was quantified by (18F)FDG-PET/CT using imaging protocols optimized for vascular assessment. The primary outcome was the between-group difference in change in maximal tissue to background ratio (TBRmax) over time, evaluated by analysis of covariance adjusted for baseline. Systemic inflammatory biomarkers were measured by enzyme-linked immunosorbent assay and a proteomic panel. Circulating immune cell phenotypes were profiled using spectral flow cytometry. Of 55 evaluable patients (mean [SD] age, 66 [10] years; 39 male [71%] and 16 female [29%]), 20 received ICIs, 15 received VEGFIs, and 20 received ICIs plus VEGFIs. At 24 weeks, TBRmax did not exceed baseline in any group (ICIs: mean [SD], 1.71 [0.14] vs 1.67 [0.14]; VEGFIs: mean [SD], 1.72 [0.22] vs 1.72 [0.17]; ICIs + VEGFIs: mean [SD], 1.74 [0.18] vs 1.64 [0.15]; among groups: P = .13). Findings were consistent across artery type, calcification status, prior atherosclerotic disease, and steroid exposure. ICI therapy was associated with selectively altered T-cell subsets, an outcome attenuated by concurrent VEGFI therapy, while VEGFI therapy alone had no significant association with circulating immune cells. Across all 3 regimens, systemic inflammatory biomarkers showed only modest changes. Intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 increased in patients exposed to ICIs. In this prospective cohort study, ICIs and VEGFIs, alone and in combination, were not associated with (18F)FDG-PET/CT-detectable arterial inflammation, and systemic inflammatory outcomes were limited. These findings argue against macrophage-driven plaque activation as a primary mechanism of ICI-associated atherothrombosis and support prioritization of endothelial and thrombotic pathways in future mechanistic and preventive studies.

Therapeutic options for advanced esophageal squamous cell carcinoma (ESCC) after first-line failure remain limited, particularly in patients previously exposed to immune checkpoint inhibitors (ICIs). We evaluated the efficacy, safety, and exploratory biomarker correlates of camrelizumab, an ICI, combined with nimotuzumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, as second-line therapy for ESCC. In this multicenter, single-arm, phase II study, patients with advanced ESCC who progressed after first-line therapy received camrelizumab (200 mg every 2 weeks) plus nimotuzumab (400 mg weekly). The primary endpoint was the objective response rate (ORR). Between November 2021 and December 2024, 46 patients were enrolled. The confirmed ORR was 32.6% (15/46; 95% CI 19.5 to 48.0) and the disease control rate was 82.6% (38/46; 95% CI 68.6 to 92.2). Median progression-free survival (PFS) was 9.13 months (95% CI 5.95 to 9.76), and median overall survival (OS) was 12.62 months (95% CI 9.40 to 15.01). Clinical activity was observed across subgroups, including immunotherapy-naïve and previously treated patients (ORR 32.0% vs 33.3%). Patients with EGFR amplification demonstrated a higher ORR (47.1% vs 24.0%) and longer median OS (13.17 vs 9.99 months). Among patients with M1 disease (n=39), the ORR was 30.8% (95% CI 17.0 to 47.6), the median PFS was 8.48 months (95% CI 5.95 to 9.59), and the median OS was 12.55 months (95% CI 7.95 to 14.88). Treatment-related adverse events occurred in 80.4% of patients, with grade ≥3 events in 8.7%. Exploratory analyses suggested that MUC16 mutations were associated with lower ORR (8.3% vs 46.4%, p=0.030), NOTCH3 mutations with prolonged survival (median PFS not reached vs 8.21 months, HR 0.20, p=0.015; median OS not reached vs 10.58 months, HR 0.22, p=0.026), and MTAP deletions with shorter PFS (3.71 vs 9.49 months, HR 3.18, p=0.005). Camrelizumab combined with nimotuzumab demonstrated encouraging antitumor activity and a manageable safety profile as second-line therapy for advanced ESCC. NCT03766178.

Immune-related adverse events (irAEs) post-immune checkpoint blockade (ICB) are a leading cause of patient morbidity. Robust peripheral biomarkers of irAEs are required to improve patient stratification to existing treatment regimens, and these are currently lacking. Seropositivity for human cytomegalovirus (CMV) is associated with protection against severe (grade 3+) irAEs post-ICB; however, the impact of infection on systemic immunity is highly variable. Here, in a prospectively recruited pan-cancer ICB-treated cohort (n=472 patients), we investigate a novel relationship between the relative baseline titer of anti-CMV IgG antibody and organ-specific protection against irAEs. Peripheral blood samples were collected from 472 patients prior to and following one cycle of ICB. CMV serotyping was performed on plasma, while flow cytometry and single-cell RNA/V(D)J sequencing were performed on peripheral blood mononuclear cells. Bulk RNA-sequencing was performed on sorted CD8+ T cells. Serological and phenotyping data were integrated with long-term clinical follow-up of response and irAEs. In CMV seropositive patients, whereas anti-CMV IgG antibody level demonstrates stability over years, high pretreatment titer is independently associated with reduced all-organ grade 3+ irAEs. This pan-organ association subdivides into organ-specific effects; protection against non-colitis irAEs being observed only in those with an above median titer of anti-CMV IgG antibody (PHigh titer vs CMV-=2.1×10-4), whereas CMV-related protection against colitis is unrelated to titer (PLow titer=0.0012, PHigh titer=0.0031). We demonstrate that anti-CMV IgG antibody titer is robustly coupled to peripheral immune subset composition, with higher anti-CMV IgG titer associated with elevated CD4+ and CD8+ T cell cytotoxicity and effector cell expansion. Conversely, CMV seropositivity is associated with generally reduced circulating Tregs cells irrespective of titer. Furthermore, we find exacerbated T cell receptor repertoire skewing toward the largest clones in High Titer individuals, with reduced survival of these clones following ICB treatment. This work reinforces the importance of CMV in modulating ICB-induced irAEs, revealing a complex relationship between the degree of humoral anti-CMV immunity and organ-specific protection, while further highlighting the clinical utility of CMV serology in predicting ICB-induced irAEs.

This review starts with the historical background and biological features to classify mainly the liquid biopsy biomarkers, such as circulating tumor DNA, circulating tumor cells, extracellular vesicles, non-coding RNAs, tumor-educated platelets and tumor-associated antigens, and also summarizes the present classification approaches and advanced detection techniques for each biomarker type. On this basis, the potential clinical uses of liquid biopsy in oncology are discussed in detail, including the early cancer detection, the prediction of the responses to chemotherapy, radiotherapy and immunotherapy, the evaluation of the treatment effects, the monitoring of the residual diseases and the investigation into the tumor heterogeneity and the resistance mechanisms. Moreover, the discussion is extended to other non-oncological fields, involving the reproduction medicine, the transplantation medicine, the neurological disorders, the infectious diseases and various chronic diseases such as the metabolic dysfunction-related liver disease and fibrosis, pulmonary fibrosis, lupus nephritis and renal fibrosis as well as rheumatoid arthritis. Finally, based on the comprehensive summary given above, this review summarizes the current status of the research on liquid biopsy, points out the main obstacles which hinder its wide application in clinic, for example, the absence of standard procedures and the necessity of large-scale prospective validation, and suggests possible future trends like the integration of multi-omics, the use of artificial intelligence in the analysis and the approach towards routine clinical practice.

On-target, off-tumor toxicity is a recurring challenge for solid tumor therapeutics targeted to antigens preferentially expressed on malignant cells. Prostate-specific membrane antigen (PSMA) is a tumor-associated antigen that is expressed on the healthy prostate and is generally upregulated in prostate cancer. It is also detected via RNA-Seq in the central and peripheral nervous system (CNS and PNS) at levels that can exceed those in the prostate itself. The CNS/PNS expression of PSMA has been largely ignored in the oncology field, and it is possible that therapeutics targeting PSMA have limited access to antigens in the nervous system. However, many PSMA-targeted therapeutics that are active in the clinic induce substantial neurotoxicity, in some cases, even treatment-associated fatalities. To protect PSMA-expressing neural tissues from on-target, off-tumor toxicity, we applied a synthetic cellular NOT gate that uses a LIR-1-based inhibitory receptor. We selected the NOT gate target antigen by searching genomic databases for a surface protein co-expressed with PSMA in the brain. Here, we demonstrate that proteolipid protein 1 (PLP1), a protein expressed on the surface of oligodendrocytes and Schwann cells, is co-expressed with PSMA in the CNS and PNS. A NOT gate construct (PSMA | PLP1 Tmod) protects human oligodendrocytes in vitro from the cytotoxicity of a PSMA CAR. Though PSMA is not expressed in mouse brains at high levels, we show that PLP1 CARs induce toxicity in mice, consistent with the possibility that CNS/PNS expression of the target of an immunotherapeutic poses a serious risk. This toxicity is mitigated by a Tmod construct (PLP1 | PLP1), in which a PLP1 CAR substitutes for a PSMA CAR, a proof of principle that circumvents the problematic expression pattern of PSMA in the mouse. Together, these findings not only highlight some of the potential risks and benefits of immunotherapy for solid tumors regarding antigens expressed in the brain, but also suggest a specific solution for PSMA CAR-Ts.

Checkpoint blockade (CPB) has limited efficacy in patients with colorectal cancer (CRC), warranting improved therapeutic strategies capable of remodeling the tumor microenvironment. Stem-like TCF1+CD8+ T cells, cytotoxic CD8+ T cells, and lymphoid aggregates have been associated with CPB responsiveness, either individually or as coordinated immune hubs. We evaluated the combination of αPD-1, the class I histone deacetylase inhibitor entinostat, and the IL-15 superagonist N-803 in CPB-resistant murine CRC and breast cancer models with varying antigen presentation deficiencies. Proteomic, transcriptomic, spatial, and functional analyses were completed to identify treatment-specific immune remodeling. Translational relevance was assessed using publicly available CPB-treated cancer genomic datasets and functional assays with patient-derived peripheral blood mononuclear cells (PBMCs). Triple therapy increased stem-like TCF1+CD8+ T cells in tumor-draining lymph nodes and tumors, concomitant with increased intratumoral cytotoxic GZMB+CD8+ T cells. Therapeutic efficacy was associated with remodeling of the tumor microenvironment, uniquely marked by enrichment of intratumoral immune niches comprising TCF1+ and cytotoxic CD8+ T cells, type 1 conventional dendritic cells, and B cells, along with concerted cytokine and chemokine production. A transcriptional signature derived from triple therapy-induced immune niches predicted favorable clinical responses across multiple CPB-experienced cancer cohorts. These responses were functionally corroborated by increased markers of cytotoxicity in patient-derived PBMCs in vitro. Treatment with entinostat, N-803, and αPD-1 boosts anti-tumor intratumoral immune niches comprising TCF1+CD8+ T cells. Collectively, these findings suggest that TCF1+CD8+ T cell immune niches previously associated with αPD-1 responsiveness and lacking in non-responders, including most CRC patients, may be restored by the addition of entinostat and N-803 to αPD-1 therapy to treat αPD-1-refractory patients.

Immune checkpoint inhibitor (ICI) resistance remains a major challenge. This review discusses emerging evidence that neuroregulation constitutes an underrecognized regulatory layer in ICI resistance and summarizes its mechanistic, biomarker, and therapeutic implications. Mechanistically, neural components can modulate antitumor immunity through signaling, structural, spatial, and metabolic routes. Neural signaling may contribute to T-cell dysfunction by stabilizing exhausted phenotypes, increasing the expression of inhibitory receptors, and suppressing effector cytokine production. Neuroglial cells and neuropeptides further exacerbate immunosuppression through the induction of regulatory T cells and the reprogramming of myeloid cells. Beyond causing functional impairment, neuroregulation alters the spatial distribution of immune cells by inhibiting chemokine networks essential for the recruitment of dendritic cells and cytotoxic T cells, thereby promoting immune-excluded and immune-cold tumor states. Neural injury creates perineural immunosuppressive niches enriched in immunoregulatory tumor-associated macrophage states and regulatory T cells, which can extend into the broader tumor microenvironment and restrict CD8+ T-cell infiltration and function. Neural inputs also reshape the metabolism of tumor and immune cells, establishing neuro-metabolic-immune circuits that limit effector cell fitness and reinforce ICI resistance. Therapeutically, pharmacological targeting of neural pathways, along with emerging bioelectronic and ex vivo neuro-immune strategies, may enhance the efficacy of ICIs across various tumor models. Neural abundance and injury signatures also emerge as potentially clinically relevant biomarkers that complement immune-centric predictors of response. Overall, neuroregulation provides a biologically coherent and potentially targetable framework for understanding and overcoming ICI resistance.

Cancers develop within a host ecosystem in which kinds of factors such as gut and tumor-resident microbiota influence the tumor microenvironment (TME) and therapeutic response. High-throughput sequencing has revealed the presence of low-biomass bacteria, fungi, and viruses across diverse malignancies, establishing the intratumoral microbiota as a fundamental TME component. However, evidence remains fragmented across descriptive associations, unclear mechanisms, and early clinical interventions, limiting casual interpretation and clinical translation. This review dissects the host-microbiota-tumor axis from intratumoral origins and colonization to pattern-recognition signaling, including TLR-NF-κB and cGAS-STING, and oncogenic networks such as Wnt/β-catenin, JAK-STAT, and PI3K-AKT. Moreover, it also discusses how microbial metabolites like short-chain fatty acids, secondary bile acids, and tryptophan derivatives reshape immune cell phenotypes and tumor cell metabolism. We then synthesize evidence linking microbiota to immune checkpoint blockade, chemotherapy resistance, radiotherapy toxicity, diagnosis, and prognosis. Finally, we compare translational strategies, including fecal microbiota transplantation (FMT), engineered bacteria, oncolytic viruses, and bacteriophages, together with their safety and standardization barriers. By connecting molecular mechanisms with preclinical and clinical evidence, this review comprehensively provides a framework for causal, biomarker-guided microbiota interventions.

Classic oncological models have largely restricted cancer pathogenesis to autonomous genetic mutations within localized cells. Current research, however, reframes solid tumors as structurally integrated "pseudo-organs" that rely on host neural networks for survival. This review examines the reciprocal signaling networks connecting nervous, immune, and malignant cells within the tumor microenvironment. At the tissue level, we outline how tumors construct de novo neural architecture via axonogenesis, cellular plasticity, and the assembly of functional neuro-neoplastic synapses. Expanding beyond the local niche, we describe the systemic brain-body circuitry. We specifically address how central nervous system pathways respond to tumor-derived cues and how chronic stress signaling disrupts physiological homeostasis. To explain the associated immune evasion, we analyze how sensory neuropeptides, particularly CGRP and, more broadly, Substance P-NK1R signaling, contribute to immune dysfunction, tumor-promoting inflammation, and therapeutic resistance. Finally, we discuss the clinical implications of these pathways. Rather than relying on nonspecific structural denervation, future therapeutic strategies should focus on targeted "neural reprogramming" to uncouple tumors from their neural dependencies and restore antitumor immunity while minimizing neurotoxicity. Ultimately, this review conceptualizes solid tumors as systemically integrated entities, establishing a framework for precision neural reprogramming to overcome immune evasion and therapeutic resistance.

CD8+ T cell dysfunction is a major obstacle to hepatitis B virus (HBV) clearance and antitumor immunity. Here, using a humanized mouse model, we identify a T cell receptor targeting a clinically relevant HBV epitope and reveal ANKRD11 as a key epigenetic regulator of CD8+ T cell dysfunction in chronic infection and tumors. Ankrd11 knockout in CD8+ T cells enhances HBV-specific T cell proliferation and effector differentiation, especially under immunosuppressive conditions, via AP-1 family gene upregulation. Loss of Ankrd11 both drives the conversion of progenitor exhausted T cells into terminally exhausted T cells, and reprograms PD-1-TOX- tolerant cells into functional effectors, improving antiviral and antitumor responses. Ankrd11-deficient T cells show increased granzyme and superior effector function, enhancing viral control and tumor regression. These findings position ANKRD11 as a promising immunotherapy target for chronic HBV infection and cancer.

Combinational photodynamic and immune checkpoint blockade (PDT/ICB) therapy is a promising approach for oncotherapy. However, the tumor microenvironment (TME) poses multiple biological barriers that can critically undermine the treatment outcomes of PDT/ICB. To this end, a cascade-amplified photodynamic immunotherapy nanoplatform based on the core-shell structured metal-organic frameworks (MOFs) was elaborately constructed. This nanoplatform, termed PMA, was constructed by growing manganese oxide (MnO2) layer on a porphyrinic MOF core, followed by conjugation with PD-L1-targeting aptamers. Upon reaching the tumor, the MnO2 shell scavenges glutathione (GSH) while concurrently releasing O2 for hypoxia alleviation and Mn2+ ions as STING agonists. Simultaneously, MOF-based core was directly self-assembled from porphyrin photosensitizers (PSs) and metal clusters, resulting in high PSs loading capacity without self-quenching. More importantly, the liberated PD-L1 aptamers block immune checkpoint interactions, reversing local immunosuppression and activating cytotoxic T lymphocytes. Together, this multimodal strategy evokes robust antitumor immunity, offering a powerful and translatable approach to expand the scope of cancer immunotherapy.

Immune suppression of tumor microenvironment (TME) limits the effectiveness of the immune therapy. Although inducing tumor cell pyroptosis and activating innate immunity are effective strategies to reverse this microenvironment, current methods are often hindered by non-targeted toxicity and the inability to precisely control drug release. To address these challenges, we synthesized an ROS-responsive R848 prodrug with a maleimide structure. Then, Hemin was coupled to bovine serum albumin (BSA) and the disulfide bonds within the BSA molecule were reduced, exposing free thiol groups. The R848 prodrug was then conjugated to the thiol groups, and the photosensitizer Ce6 was loaded, allowing self-assembly into the HBSA@CR nanoagonist. This strategy not only achieved a higher drug loading capacity than traditional albumin nanoparticles, but also retained the biocompatibility of natural albumin and the advantages of receptor-mediated cellular uptake. HBSA@CR can be activated by 660 nm laser irradiation to efficiently generate ROS through photodynamic and enzymatic catalysis. In vitro experiments show that this nanoparticle can efficiently kill tumor cells, induce pyroptosis through the Caspase-3/GSDME pathway and trigger the release of R848. In tumor-bearing mouse models, HBSA@CR effectively inhibited primary tumor growth and lung metastasis, and reprogrammed the immunosuppressive TME. In a tumor rechallenge model, this strategy prevented tumor recurrence and conferred long-lasting immunological memory. Moreover, when used in combination with the immune checkpoint inhibitor αPD-L1, this nanoparticle exhibits synergistic therapeutic effects. The designed nanoagonist offers a biomimetic platform for combined photo-immunotherapy, which achieves controlled R848 release while inducing tumor cell pyroptosis, reprogramming the immunosuppressive TME, and eliciting durable antitumor immunological memory. STATEMENT OF SIGNIFICANCE: The immunosuppressive tumor microenvironment is one of the main obstacles to effective immunotherapy, severely restricting the clinical efficacy. Inducing pyroptosis and stimulating innate immune activation are effective strategies for reprogramming the tumor microenvironment, but existing methods often face problems such as the lack of selectivity in inducing pyroptosis and the high toxicity of systemic administration of immune agonists. In this study, a nanoagonist HBSA@CR was constructed, which retains the biocompatibility and receptor-mediated tumor uptake of native albumin. This nanoplatform utilizes ROS to induce tumor cell pyroptosis and drive the controlled release of R848, achieving precise local pyroptosis induction and innate immune activation, effectively reprogramming the immunosuppressive microenvironment and stimulating persistent anti-tumor immune memory.

Tumor-associated neutrophils (TANs) are increasingly recognized as heterogeneous and context-dependent regulators of cancer progression and treatment response. Through cytokine secretion, protease release, oxidative activity, and formation of neutrophil extracellular traps (NETs), TANs remodel the tumor microenvironment (TME) and influence immune regulation, angiogenesis, invasion, and metastasis. Recent advances in molecular imaging enable selected neutrophil-associated molecular processes to be monitored in vivo using optical, photoacoustic, chemiluminescent, and magnetic resonance approaches. These approaches include neutrophil elastase (NE) activity-responsive imaging, NETosis-related imaging, and myeloperoxidase (MPO) activity-responsive imaging. These readouts provide spatially and temporally resolved information on neutrophil-associated molecular activity and, when combined with complementary cellular, histological, and functional analyses, support more robust characterization of the underlying cellular sources and biological functions. In parallel, neutrophil-directed treatments seek to limit recruitment, suppress or reprogram protumor functions, and inhibit NET formation or promote NET clearance. Neutrophils and neutrophil-derived materials are also being developed as drug-delivery platforms, including live or engineered neutrophils, neutrophil membrane-coated nanocarriers, and extracellular vesicles. This review summarizes advances across these areas and discusses how imaging readouts relate to biological interpretation, candidate interventions, confirmatory assessments, therapeutic outcomes, and safety. Although current evidence remains predominantly preclinical and context dependent, integrating molecular imaging with cellular phenotyping, functional validation, and longitudinal outcome assessment may support more selective and adaptive neutrophil-centered strategies for precision oncology.

T regulatory cells (Tregs) come in different flavors, but they all share suppressive function and the role in the generation and maintenance of immune tolerance. Due to this essential activity, Tregs are targets for immunotherapy: Tregs promotion is wanted in pathological conditions such as autoimmunity, allergies and transplantation, whereas their elimination is the main goal in the context of cancer. Transplantation is the only treatment available when organ failure is detected but unfortunately transplant rejection has not been fully achieved regardless of all efforts made, such as the identification and use of new immunosuppressant drugs and biological therapies. During the last two decades, Tregs have become a cellular source for therapy to control primarily Graft-versus-Host Disease (GvHD) -in the case of cellular transplantation- and rejection of solid allografts as in liver and kidney transplants. Like in other biomedical disciplines, many advances applying immunological technologies only reach the patients if developed in the north hemisphere, and transplantation is not an exception. Here, we present the contribution of Latin America (LATAM), regarding solid organ transplantation from basic and clinical immunology research, focusing on Tregs as the main topic of study.

The efficacy of immune checkpoint blockade (ICB) in lung adenocarcinoma (LUAD) is limited by primary or acquired resistance, especially in genetically defined subsets. We investigated the impact of KRAS/TP53 co-mutation on ICB response. Our analysis reveals that KRAS/TP53 co-mutation is associated with favorable ICB outcomes, a phenotype orchestrated by secreted phosphoprotein 1 (SPP1). Mechanistically, mutant p53 and KRAS exert opposing effects on SPP1. Mutant p53 synergizes with transcription factor FOXA1 to repress SPP1 transcription, whereas KRAS activates the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)-signal transducer and activator of transcription 1 (STAT1) axis to up-regulate SPP1. Consequently, reduced SPP1 level in KRAS/TP53 co-mutant LUAD impairs myeloid-derived suppressor cell (MDSC) recruitment and increases CD8+ T cell infiltration. Notably, SPP1 blockade synergizes with anti-programmed death-1 (PD-1) therapy to suppress tumor growth in KRAS-mutant xenograft models. Collectively, we delineate a mutant p53-FOXA1-SPP1 regulatory axis that modulates ICB susceptibility and unveil a synergistic combination therapy strategy.

The immunosuppressive tumor microenvironment (TME) remains one of the main obstacles that limit responsiveness to immunotherapy. Recently, lipid nanoparticles carrying messenger RNA (mRNA) have emerged as a promising strategy to modulate the immunosuppressive TME, with the ultimate goal of sustaining anticancer immunity of cytotoxic T lymphocytes (CTLs). However, there are challenges with mRNA-based cytokine/chemokine therapies such as the lack of specific targeting, low therapeutic efficacy, and elevated toxicity, raising concerns about their clinical translation. Here, we have developed an antibody-coated lipid nanoparticle (Ab-LNP) delivery system that targets the protein triggering receptor expressed on myeloid cells 2 (TREM2) expressed by tumor-associated macrophages (TAMs). We demonstrate that codelivery of a Toll-like receptor agonist and CXCL9-encoding mRNA encapsulated in our Ab-LNP successfully ameliorates immunosuppression and improves tumor infiltration and activity of CTLs. Further combination with immune checkpoint inhibitors against PD-L1 and CTLA-4 promoted a CTL-favoring immunological environment and durable memory immunity. Our Ab-LNPs targeting TAMs highlight the potential of reprogramming immunosuppressive TME to enhance CTL activity for improved response to cancer immunotherapy.

Extracellular matrix (ECM) stiffness is known to impair T cell function, yet the underpinning molecular cascade remains undefined. This paper investigates the role of lysyl oxidase-like 4 (LOXL4) in ECM stiffening and CD8+ T cell function in lung cancer. Loxl4 knockout and mouse recombinant LOXL4 protein systems, along with Piezo1, Ybx1, Acly, and Kat2a conditional knockout mouse models were established. ECM stiffness was measured by atomic force microscopy, and T cell exhaustion markers were analyzed using flow cytometry. RNA sequencing, ATAC-seq, CUT&Tag, chromatin immunoprecipitation-quantitative polymerase chain reaction, and luciferase assays were used to explore the underlying molecular mechanisms. Molecular docking was performed to explore Food and Drug Administration-approved agents targeting LOXL4. The results demonstrated that tumor-derived LOXL4 stiffened the ECM, which activates the mechanosensor Piezo1 in CD8+ T cells, triggering Ca2+ influx and downstream FAK1-YAP1 signaling. Nuclear YAP1 transactivated YBX1, which recruited the metabolic enzyme ACLY and the histone acetyltransferase KAT2A to exhaustion gene loci, epigenetically reinforcing terminal exhaustion. Conditional knockout of Piezo1, Ybx1, Acly, and Kat2a in murine CD8+ T cells abolished stiffness-induced exhaustion and suppressed tumor growth. Acetyldigoxin was identified as a high-affinity LOXL4 inhibitor. It softened the ECM, disrupted the mechanosignaling-epigenetic axis, reversed CD8+ T cell exhaustion, and synergized with anti-PD-1 blockade to achieve durable tumor regression. In conclusion, this study uncovers a mechanotransduction-to-epigenetic pathway where LOXL4-driven matrix stiffening induces CD8+ T cell exhaustion. Repurposing acetyldigoxin as a LOXL4-targeted therapy offers a promising clinical strategy to overcome ECM-mediated immunotherapy resistance in lung cancer.

Within solid tumors, stromal barriers and immune exclusion limit the success of immunotherapies. Thus, novel therapeutic approaches are required to remodel the tumor-supportive microenvironment and enhance therapeutic responses. We developed a bispecific, trivalent Fab-eIg T cell engager (OMTX305) targeting fibroblast activation protein (FAP), a marker of tumor-promoting cancer-associated fibroblasts. The translational potential of OMTX305 was investigated in 2D and 3D patient-derived preclinical models, with a focus on precision-cut tumor slices (PCTSs) of lung and ovarian cancer cocultured with autologous PBMCs. By combining spatial biology with cytokine and transcriptomic analysis, we show that OMTX305 treatment eliminated FAP-expressing fibroblasts, induced interferon responses and extracellular matrix remodeling, ultimately triggering bystander killing of adjacent tumor cells. Distinct immune phenotypes and PD-L1 expression patterns appeared to be associated with differential treatment responses, suggesting their potential as biomarkers for patient stratification. Our findings highlight the clinical potential of targeting stromal elements as a cancer therapy and establish PCTS as a powerful preclinical platform for personalized immunotherapy assessment.

Cytokines are powerful modulators of antitumor immunity, but their clinical use is limited by structural instability, short half-life, poor drug-like properties, and severe systemic toxicity. Antibody-based cytokine mimetics have recently emerged to activate immune cells in vitro, but whether these mimetics can overcome the shortcomings of cytokines and exert therapeutic efficacy in vivo remains unclear. Here, we engineered bispecific antibody-based IL-15 mimetics using immunized Alpaca-derived phage display coupled with AlphaFold3-assisted structural screening and comparative screening of multiple formats to identify tandem IL-15 mimetics with strong in vitro bioactivity. Importantly, tandem IL-15R agonistic bispecifics, which simultaneously engage IL-15Rβ and γc, clearly demonstrated antitumor activity in vivo. To better target tumor-infiltrating lymphocytes (TILs), we incorporated a high-affinity anti-TIGIT antibody to guide tandem IL-15Rβγ agonists. This tri-antibody design, αTIGIT-αIL-15Rβγ, resulted in a striking improvement in antitumor activity without detectable systemic toxicity even at high doses. Mechanistically, αTIGIT-αIL-15Rβγ enhanced CD8⁺ T effector function and expanded the number of intratumoral stem-like T cells. Our study highlights a strategy to use TIL-targeted cytokine mimetics to overcome the limitations of native cytokines and enable dose pairing with immune checkpoint blockade (ICB), offering a path toward safer and more effective cytokine immunotherapy.

T cell receptor (TCR)-based immunotherapy is limited by tumor antigen heterogeneity, which frequently leads to relapse. We developed a bispecific TCR-JANUS engager that functions synergistically with TCR engineered T cells (TCR-T). In contrast to conventional T cell engagers targeting CD3, TCR-JANUS engages both the variable region of a transgenic TCR (TRBV) and a tumor surface antigen. Using a model system targeting a humanized KRAS-G12V-specific TCR and trophoblast cell surface antigen 2 (Trop2), we show that TCR-JANUS effectively redirects TCR-T cells to lyse Trop2-expressing tumor cells while preserving intrinsic specificity toward the cognate pHLA target, thereby enabling simultaneous dual-antigen recognition. In heterogeneous tumor models, the combination of TCR-JANUS with TCR-T cells, an integrated system termed T Cell Dual Arsenal Recon, potently suppressed tumor growth by clearing antigenically divergent populations. Moreover, TCR-JANUS maintained enhanced T cell functionality with reduced exhaustion compared to anti-CD3-based engagers upon chronic stimulation. Together, this approach offers a targeted and durable strategy to overcome antigenic heterogeneity, expanding the clinical prospects of TCR-T cell therapy for solid tumors.

Cancer immunotherapy is frequently hindered by the immunosuppressive tumor microenvironment. Although metal ions have been viewed as essential nutrients or cytotoxic payloads, emerging evidence reveals that they are potent immune modulators that orchestrate the cancer-immunity cycle. Here, we synthesize how ionic competition dictates immune cell plasticity and metabolic fate. We detail how metal ions regulate cell death pathways and immune signaling cascades, including the cyclic GMP-AMP synthase-stimulator of interferon genes and nuclear factor kappa B pathways, as well as immunological synapse formation and immune cell responses. Finally, we evaluate the clinical potential of targeting the metal ions-immune axis, from metallomic biomarkers, including Zrt-/Irt-like protein transporters and ion channels, to metallo-immunotherapy strategies. This framework provides a mechanistic roadmap for developing combination therapies to overcome immunotherapy resistance and harness the cellular metallome for precision oncology.

Fungi have been detected within human tumors and shown to support tumor progression. A better understanding of how intratumoral fungi evade innate immunity, remodel the tumor microenvironment (TME), and promote tumorigenesis may provide insights into cancer pathogenesis and therapeutic strategies. Here, we showed that aggressive human head and neck squamous cell carcinomas (HNSCCs) harbor an elevated fungal burden, including the environmental fungus Cladosporium cladosporioides, and are infiltrated by IL1B-high neutrophils with impaired reactive oxygen species (ROS) production and phagocytosis, as well as IL1B-high macrophages. In a mouse model in which Ikka ablation drives tumorigenesis through EGFR and STAT3 activation, oral C. cladosporioides infection recapitulated key features of the human HNSCC TME, elevated serum IL-1β and IL-17A levels, and promoted both oral and skin SCC development. Oral fungal infection also increased the acidic metabolites uric acid and lactate in the TME. These metabolites enhanced C. cladosporioides-induced IL-1β production while reducing ROS production in neutrophils, thereby impairing fungal clearance. Mechanistically, C. cladosporioides, IL-1β, and IL-17A activated STAT3 and cyclin D1 signaling in SCC cells. Epithelial Stat3 deletion abrogated both Ikka loss-driven and fungus-enhanced oral and skin carcinogenesis, reduced macrophage accumulation, restored normal oral neutrophil phenotypes, and cleared oral fungal infection. Furthermore, IL-1β induced by C. cladosporioides inoculation drove systemic inflammation that promoted skin SCC via an IL-1β/IL-1R feedback loop involving neutrophils and macrophages. Together, these findings identify a fungus-driven immunosuppressive circuit in which tumor-derived acidic metabolites impair antifungal immunity, thereby promoting both local and distal SCC progression.

Cancer-associated fibroblasts (CAFs) foster an immunosuppressive tumor microenvironment (TME) and confer resistance to immune checkpoint blockade (ICB) in gastric cancer (GC). However, the mechanisms by which specific CAF subsets regulate metabolic crosstalk and immune evasion remain poorly defined. We integrated bulk and single-cell RNA-sequencing data, spatial transcriptomics, and clinical cohorts of GC patients treated with immunotherapy. Functional validation was performed using in vitro co-culture systems, multiple murine models, and lipid nanoparticle (LNP)-encapsulated siRNA targeting Postn. We identified POSTN + CAFs as a key subset enriched in ICB non-responders and associated with poor prognosis. Mechanistically, POSTN secreted by CAFs engaged integrin β1 (ITGB1) on tumor cells and macrophages, activating the PI3K/AKT/mTOR signaling axis and upregulating PPARγ. This signaling cascade drove lipid metabolic reprogramming, characterized by increased lipid accumulation and oxidative stress, and promoted the polarization of macrophages toward an immunosuppressive, lipid-stressed M2 phenotype. Targeting POSTN signaling with LNP-formulated siPostn attenuated tumor growth, suppressed lipid metabolism, and reduced M2 macrophage infiltration in the TME. This work reveals that POSTN + CAFs establish an immunosuppressive TME and are associated with ICB non-response in GC by remodeling lipid metabolism through the ITGB1-PI3K/AKT/mTOR-PPARγ axis, a finding that underscores the therapeutic value of intervening in this specific CAF-macrophage metabolic crosstalk.

Glioblastoma (GBM) is an aggressive brain malignancy with a median survival of only 15 months despite current therapeutic interventions. A major obstacle to effective treatment is the intricate tumor microenvironment (TME), which drives tumor progression and therapy resistance. However, existing in vitro models lack micrometer-scale spatial control over multiple cellular components and fail to preserve their dynamic interactions, limiting our understanding of tumor biology and treatment responses. Here, we present a spatially controlled GBM-on-a-chip (scGoC) platform that integrates a novel organoid positioning strategy, enabling the reconstruction of the TME within a 3D matrix at micron-level precision. This platform allows real-time monitoring of dynamic tumor-immune-vascular interactions, providing refined insights into tumor progression and drug responses. Using the scGoC, we demonstrate that endothelial cells not only promote microglial migration toward tumor organoids but also drive their polarization toward an immunosuppressive phenotype, faithfully recapitulating hallmark features of GBM progression. Importantly, the platform reveals a pro-tumorigenic adaptive response to bevacizumab monotherapy, driven by the upregulation of HIF-1 signaling and metabolic reprogramming pathways, providing mechanistic insights into GBM treatment. Collectively, the scGoC establishes a versatile and standardized tool for decoding complex cellular communications and investigating mechanisms of treatment response with broad applicability across cancer research.

Systemic anti-tumour immunity results from T cell priming in tumour-draining lymph nodes (TDLNs)1-4. Although the suppression of T cells in tumours is well characterized5-8, whether this occurs in TDLNs-and if so, through which mechanisms-remains poorly understood. Here, using imaging mass cytometry of TDLNs from patients with melanoma, we identify a spatial neighbourhood in the TDLN paracortex that is linked to the development of distant metastases. Targeted spatial transcriptomics of cells inside this neighbourhood revealed activated CD8+ T cells engaging with myeloid cells that expressed high levels of the immunosuppressive secretory phospholipase PLA2G2D. PLA2G2D+ myeloid cells were substantially more abundant in TDLNs than they were in primary tumours or metastases. Genetic loss-of-function or antibody-mediated inhibition of PLA2G2D reduced tumour growth markedly, and single-cell transcriptomics in melanoma-bearing mice revealed that expression of Pla2g2d is confined to lymph-node macrophages. Mechanistically, PLA2G2D directly suppressed the early proliferation of T cells in vitro, and inhibiting PLA2G2D resulted in an expansion of tumour-specific T cells in TDLNs, leading to an increase in these T cells in the circulation and subsequently in tumours. Notably, PLA2G2D and PD-1 act as non-redundant immune checkpoints, with combination treatment showing additive or synergistic efficacy in humanized mice treated with human-specific antibodies. Collectively, our in-depth spatial profiling identifies PLA2G2D as a TDLN-centred targetable immune checkpoint for cancer immunotherapy.

Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1-4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

Tumors co-opt normal wound-healing programs to shape their immune microenvironment, yet how distinct immune states arise and influence therapy remains unclear. Here, we synthesize emerging evidence that tumors become locked in either proinflammatory or pro-resolution phases, defined by neutrophil- or macrophage-dominated ecosystems. These states not only remodel local tissues but also systemically reprogram hematopoiesis, creating self-reinforcing immune circuits that drive progression, metastasis, and treatment resistance. We highlight recent advances linking epithelial-mesenchymal plasticity, lipid metabolism, and myeloid dynamics into an integrated 'wound-healing clock' model. This framework provides a conceptual basis for patient stratification and suggests that therapeutically redirecting immune states may unlock new strategies to overcome resistance across cancer types.

Gastric cancer (GC) derives limited benefit from immunotherapy, with clinical responses observed in only a minority of patients. Increasing evidence suggests that heterogeneity within the tumor immune microenvironment (TME) is a critical determinant of immunotherapeutic efficacy, highlighting the need for precise immune stratification and the identification of molecular biomarkers that shape the TME. We integrated single-cell transcriptomic data from our cohort and public datasets to characterize immune microenvironment heterogeneity in GC. Functional experiments were performed using in vitro assays and in vivo mouse models to investigate the molecular mechanisms regulating immune exhaustion. Clinical relevance was evaluated using tumor specimens from patients with GC receiving anti-programmed cell death protein 1 (PD-1) therapy. Survival analyses and biomarker evaluation were conducted to assess the prognostic and predictive value of candidate markers. We identified two distinct GC immune microenvironment subtypes: the immunosuppressive (GC1) and the immune-activated (GC2). PRKX was identified as a key regulator associated with immune heterogeneity and exhaustion. Clinically, a high density of PanCK+ PRKX+ PD-L1+ tumor cells was significantly associated with poor prognosis and served as a robust biomarker predicting 5-year survival in patients treated with anti-PD-1 therapy. Mechanistically, PRKX phosphorylates programmed death-ligand 1 (PD-L1) at T285, promoting YWHAE recruitment and preventing UBE2M-mediated ubiquitination and degradation, thereby stabilizing PD-L1 protein. Through this phosphorylation-dependent regulation of PD-L1 stability, PRKX suppresses CD8+ T-cell cytotoxicity, promotes immune exhaustion, and limits the efficacy of anti-PD-1 therapy in vivo. Therapeutically, lipid nanoparticle-mediated delivery of PRKX-targeting siRNA effectively suppressed PRKX expression and synergized with anti-PD-1 therapy to enhance antitumor efficacy. PRKX drives immune exhaustion in the GC1 subtype by stabilizing PD-L1 through phosphorylation-dependent inhibition of ubiquitination, thereby promoting immune evasion. Targeting PRKX represents a potential strategy to overcome resistance to anti-PD-1 therapy, and PRKX expression may serve as a prognostic biomarker to guide immunotherapy in GC.

Aberrant angiogenesis is a hallmark of cancer that promotes tumor progression and therapeutic resistance. The resulting tumor vasculature is structurally and functionally abnormal, leading to inadequate perfusion and hypoxia. Beyond supporting tumor growth, such vascular abnormalities also restrict immune cell infiltration and impair antitumor immune responses. Accordingly, tumor vasculature emerges as a potential target to improve therapeutic outcomes. This review summarizes the cellular composition, functional heterogeneity, and diverse types of tumor vasculature, as well as the crosstalk between abnormal blood vessels and immune cells. We further outline the current vascular-targeting approaches, with a particular focus on their immunomodulatory effects and synergistic potential with immunotherapies. Diagnostic classification of tumor vasculature, together with the combination of vascular-targeted therapy and immunotherapy, may offer new opportunities for precision tumor treatment.

Cancer pain is increasingly recognized as an active output of tumor-nerve-immune biology rather than a passive consequence of tissue damage. Tumor-derived algogens, neurotrophic factors, stress signals and immune mediators can sensitize nociceptors, facilitate perineural invasion, remodel myeloid and lymphoid compartments and recruit central glial mechanisms that may maintain persistent pain. However, the evidence base is asymmetric: many causal circuits were defined in selected bone-metastasis, perineural-invasion, oral-cancer, sarcoma or chemotherapy-induced neuropathy models, whereas applicability to human cancer pain varies by tumor type, pain phenotype, immune contexture and treatment exposure. This critical narrative Review evaluates peripheral, central, immune and pharmacological evidence using explicit model-to-human boundaries. Recent patient studies in oral squamous cell carcinoma link pain with CGRP-positive nerve density, circulating or tissue CGRP, perineural invasion and reduced CD8-positive T-cell density, but these associations do not establish human causality; validated biomarkers of spinal glial mechanisms are still lacking. We examine druggable nodes including NGF-TrkA, SLIT2-ROBO1, CGRP-CALCRL/RAMP1, CSF1R-dependent myeloid or glial signaling, voltage-gated sodium channels and opioid-neuroimmune interactions. Clinical trial and cohort examples illustrate therapeutic paradoxes in which analgesia must be balanced against joint safety, tissue repair, host defense and potentially confounded associations with immunotherapy outcomes. We finally propose a phenotype-matched model-selection framework and a druggable circuit-state strategy for patient-stratified pharmacological development.

Metabolic reprogramming and resistance to regulated cell death (RCD) are central features of the tumor microenvironment (TME) that drive therapeutic failure. Emerging evidence indicates that neurotransmitter signaling networks-including glutamate, dopamine, 5-hydroxytryptamine (5-HT), and norepinephrine-extend beyond neural communication to function as critical regulators of tumor metabolism, immune modulation, and cell fate. These neurotransmitters influence multiple RCD modalities, such as ferroptosis, cuproptosis, and PANoptosis, through interconnected metabolic and signaling mechanisms. Glutamate is explicitly resolved by compartment and route: high extracellular glutamate inhibits System Xc⁻, restricts cystine uptake and glutathione synthesis, and promotes ferroptosis, whereas intracellular glutamate production, glutaminolysis, SLC7A11-coupled glutamate export, and receptor-mediated signaling have distinct, context-dependent consequences. Dopamine and 5-HT exert context-dependent effects through receptor subtype-specific metabolic rewiring. Sympathetic neurotransmitters, including norepinephrine, enhance glycolysis and lactate-driven immunosuppression through β₂-adrenergic signaling. In parallel, the gut-brain axis modulates tumor susceptibility to RCD by shaping the availability of microbiota-derived neurotransmitter precursors and metabolites. Mechanistically, neurotransmitter signaling converges on RCD programs by regulating redox homeostasis, lipid peroxidation, mitochondrial vulnerability, and inflammatory signaling. Integrating these observations, this review proposes a conceptual framework termed the "Neurotransmitter-Novel Cell Death-Gut-Brain Axis," which links neural signaling, microbial metabolism, and tumor cell death decisions. Building on this framework, we highlight therapeutic strategies combining receptor-subtype-specific neurotransmitter modulation with selective induction of RCD pathways to overcome metabolic plasticity, immune evasion, and therapy resistance. Targeting this integrated neuro-metabolic-death network may offer a clinically actionable avenue to enhance tumor sensitivity to existing and emerging anticancer therapies.

Nitric oxide (NO) holds promise for circumventing resistance to platinum-based chemotherapy by reprogramming the tumor microenvironment (TME) in lung adenocarcinoma (LUAD). However, their further application is greatly hindered by uncontrolled release kinetics and off-target toxicity. Herein, an inhalable NO nanogenerator (10m@FOMs-Cu) that reprograms the TME via specific NO release is developed by encapsulating a biorthogonal-activated NO-cisplatin prodrug into TME-responsive hybrid micelles, allowing for sustained and effective LUAD treatment. The prodrug integrates a Pt-based catalyst with a caged active NO donor within one molecule and is further encapsulated in a disulfide-cross-linked organosilica shell, enabling redox-triggered self-catalytic NO release while minimizing off-target injury to normal tissues. It is verified that nebulized 10m@FOMs-Cu could achieve efficient mucus-extracellular matrix dual barrier penetration to reach the TME, thereby ensuring sustained NO release to potentiate Pt(II)-mediated nuclear damage and Cu(II)/Cu(I)-mediated cuproptosis. This sensitization process reprograms the TME by inducing metabolism-DNA stress feedback, triggering a systemic and durable immune response that confers efficient tumor suppression in orthotopic and rechallenged LUAD. It demonstrates that 10m@FOMs-Cu could serve as a potent and safe nebulized nanomedicine for LUAD therapy and provides insights into designing gas-based nanotherapeutics.

Photosensitizers in nanocrystals have emerged as promising avenues for immune stimulation through enhanced reactive oxygen species (ROS) generation relative to their amorphous structures. However, their rigid molecular packing severely restricts the molecular variations necessary for stimuli-responsive conversion in the crystalline state, resulting in challenges for these nanocrystals to undergo dynamic and on-demand immune regulation, particularly under the tumor microenvironment (TME) stimulation. Herein, we address this challenge by developing 2TZP, a photosensitizer engineered with a synergistic proton-capturing motif that confers a narrow pH response range within the TME. This design enables a specific and complete acid-triggered nanocrystal-to-nanocrystal (NCNC) transformation, from hexagonal prism to cuboid prism, directly activated by TME (pH 6.5) with a narrow response range of 0.70 pH units. This process involves significant conformational distortion, subtle rotation, and slippage within the preserved crystalline lattice, which is favored by sensitive responsiveness, sufficient free volume, and crystal lattice similarity before and after nanocrystal transformation. Crucially, this mechanism serves a dual purpose. It intensifies the twisted intramolecular charge transfer (TICT) effect, boosting intersystem crossing (ISC), while simultaneously unveiling latent RNA binding to form an electron reservoir pump and thereby enhancing ROS generation. Thus, the transformed 2TZP nanocrystals further potentiate their ability to target the nucleolus, causing oxidative damage to the nucleolus and leading to pronounced nuclear disruption and enhanced dsDNA leakage. This then effectively ensures potent, on-demand activation of the cGAS-STING immune pathway while concurrently inducing robust immunogenic cell death (ICD) under an acidic TME. This work not only demonstrates a model of NCNC transformation within the TME, but also establishes a design principle to couple structural regulation with dynamic, on-demand function amplification for potential photoimmunotherapy.

The topological characteristics of microbial surfaces play pivotal roles in immune responses. However, integrating adjuvants and antigens to construct nanovaccines that mimic pathogenic surface nanostructures, especially for antigen delivery and immune activation, remains unexplored. Herein, we systematically investigated the antigen delivery efficiency and immunostimulatory capacity of nanovaccines with distinct morphologies: MO@SP (spherical), MO@ST (fibrous), MO@LA (lamellar), and MO@VLP (rough-surfaced spiky-like), synthesized through the self-assembly of manganese ions (Mn2+) with antigen peptides. These nanovaccines were designed to evaluate their potential for efficient antigen delivery and immune activation, with a particular focus on how their structural properties influence cellular uptake and immunogenicity. Among the different morphologies, MO@VLP exhibited superior internalization by dendritic cells (DCs) via caveolae-dependent endocytosis and F-actin-mediated pathways, followed by efficient lysosomal escape and antigen release into the cytoplasm, facilitating antigen cross-presentation due to its distinctive spike-like structure. Notably, MO@VLP, akin to viral surfaces, induced cytoskeletal rearrangement and activated Toll-like receptor (TLR) signaling pathway, ultimately leading to DC maturation. Moreover, MO@VLP markedly enhanced nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) inflammatory signaling, promoting strong tumor-specific immune responses. Compared to nanovaccines with other morphologies, MO@VLP showed significantly enhanced tumor-preventive efficacy in the B16-OVA tumor model. Meanwhile, in combination with immune checkpoint blockade (ICB) therapy, MO@VLP provoked potent antigen-specific cellular immune responses, significantly suppressed tumor growth, and extended survival to 67 days in murine models. This study underscores the structure-dependent effects of metal-coordinated antigenic nanoarchitectures in immune activation and highlights the potential of adjuvant-functionalized, spike-mimetic nanovaccines for cancer immunotherapy.

Mucosal immunity-the body's frontline defense, harboring 80% of the body's immune cells-represents a potent yet underexploited avenue for cancer vaccination. Here, we developed an oral biohybrid vaccine platform by integrating tumor antigen-loaded liposomes with fimbriae-enriched bacteria (Escherichia coli or VNP20009) through bacterial hitchhiking or membrane hybridization. These biohybrids promote mucosal antigen delivery via glycoprotein 2 (GP2)-mediated microfold-cell (M-cell) transcytosis, enhancing antigen cross-presentation and activation of a mucosa-periphery-tumor immune cascade. Bacterial membrane-hybridized vaccines outperform bacteria-hitchhiking counterparts by reconfiguring dendritic cell (DC) subsets within gut-associated lymphoid tissues (GALTs) and triggering C-C chemokine receptor type 7 (CCR7)-dependent immune cell trafficking, thereby propagating mucosal immune activation toward distal tumor microenvironment (TME) reprogramming and tumor control. When combined with PD-1 blockade, this strategy enhances antitumor efficacy by promoting effector cell mobilization and establishing memory against tumor rechallenge. Collectively, these findings position bacteria-derived arsenal biohybrids as a versatile oral vaccine strategy, advancing mucosal immunotherapy for cancer.

Recurrence and peritoneal metastasis remain major challenges in gastric cancer (GC), highlighting the need to identify actionable stromal-tumor signaling circuits within the tumor microenvironment (TME). Integrated transcriptomic analyses and clinical validation identified TAGLN as a fibroblast-enriched factor associated with GC progression and poor prognosis. Functional studies showed that TAGLN expression in cancer-associated fibroblasts (CAFs) enhanced HGF production, at least in part through NF-κB activation, thereby promoting GC-cell malignant phenotypes via paracrine HGF/c-MET signaling. Mechanistically, HGF/c-MET activation promoted DDX5 phosphorylation, with Tyr595 identified as a critical phosphorylation site, and increased DDX5 nuclear accumulation. Nuclear DDX5 was enriched at the CAV1 promoter and enhanced CAV1 transcription, whereas CAV1 promoted malignant phenotypes by activating the PI3K/AKT/mTOR signaling. Salvianolic acid A (SA-A) showed TAGLN target engagement in DARTS and CETSA assays and attenuated TAGLN-associated CAF activity. In vivo, SA-A suppressed CAF-driven tumor growth and peritoneal dissemination. Collectively, these findings define a CAF-TAGLN/HGF/c-MET/DDX5/CAV1 signaling cascade linking stromal activation to tumor-cell transcriptional reprogramming and CAF-tumor crosstalk within the TME, and identify TAGLN as a potential therapeutic vulnerability for microenvironment-directed intervention in GC.

Accumulating evidence implicates sensory neurons in tumor progression, but signals linking nociceptive activity to impaired antitumor immunity remain unclear. In a recent issue of Cell, Ho et al. show that nociceptor activation impedes TLS assembly through CGRP, and cigarette smoke engages this neuroimmune axis, promoting tumor growth independently of mutagenic effects.

Aberrant extracellular matrix (ECM) remodeling in tumors is characterized by altered deposition, enzymatic cross-linking, degradation, and organization of matrix molecules that in turn can contribute directly to tumor invasiveness, immune evasion, and resistance to therapy. Traditionally, cancer-associated fibroblasts (CAFs) have been considered the principal architects of ECM remodeling in tumors. However, the role of non-fibroblast cell populations in modulating ECM structure and function and how these processes intersect with immune regulation, metabolism, and metastasis is also crucial but currently underappreciated. Challenging the prevailing fibroblast-centric paradigm, this review provides an overview of how non-fibroblast cell types engage in dynamic crosstalk and collectively shape the biochemical and biomechanical landscape of tumors. Therapeutic strategies targeting these alternative stromal players could disrupt pro-tumor ECM dynamics, enhance anti-tumor immunity, and restore tissue homeostasis. Thus, a comprehensive understanding of the intricate network of non-fibroblast stromal cells within the tumor microenvironment (TME) can help elucidate opportunities for precision medicine and personalized cancer care, leading to the development of innovative therapeutic interventions targeting the TME.

Obesity is a global health concern, driving metabolic dysfunction and systemic inflammation. Here, we review the current understanding of the mechanisms underlying the impact of obesity in cancer susceptibility, progression, and response to therapy. We first discuss how resident and recruited macrophages adapt to metabolic stress within adipose tissue and the liver, which are metabolic hub tissues. We consider how obesity-driven myeloid reprogramming extends to other myeloid lineages and influences systemic immune function. Within this framework, where myeloid cells play conserved roles across tissues, we discuss cancer and how obesity-imprinted programs modify antitumor immunity irrespective of tumor site. We propose that local metabolic adaptation results in systemic immune consequences that impact tumor development and progression. Viewing cancer through the lens of obesity-related immunometabolic dysfunction may shed light on tissue- and cancer-specific responses and open avenues to improved therapies and management.

Developing a "full-cycle" strategy that integrates both treatment and prophylaxis remains a central challenge against nasopharyngeal carcinoma (NPC). Here, a biomimetic nanovaccine (CDC/Toy@CCM) is designed by coating toyocamycin (Toy)-loaded redox-responsive carbon dot clusters (CDCs) with homologous cancer cell membranes (CCMs). The obtained nanovaccine exhibits an average size of 70.7 nm, a high drug loading capacity (12.3%), and a superior photothermal conversion efficiency of 48.7%. The nanovaccine leverages the homologous targeting capacity of CCMs for precise tumor homing, while the disulfide-cross-linked CDCs enable glutathione-triggered drug release specifically within the tumor microenvironment for controlled chemotherapy. Under near-infrared laser irradiation, the CDCs generate robust photothermal ablation of primary tumors, and the combination of chemotherapy and photothermal therapy (PTT) effectively induces immunogenic cell death (ICD), which synergizes the self-adjuvant of CDCs and CCM antigens to generate significant antitumor response to suppress both primary and distant tumors in a bilateral NPC mouse model. In a prophylactic setting, the nanovaccine pre-vaccination generates effective immune protection against subsequent tumor challenge. This work provides a promising "full-cycle" nanoplatform that synergistically integrates PTT, chemotherapy, and immunotherapy for both NPC treatment and prophylaxis.

The cGAS-STING pathway is a pivotal therapeutic target for antitumor immunity, yet clinical translation of its small-molecule agonists is hindered by poor tumor specificity, suboptimal pharmacokinetics, and systemic off-target effects. Here, we report a nanocatalytic strategy based on a tumor microenvironment (TME)-responsive iron-oxygen-vanadium metal-organic framework (MIL-88B(Fe─O─V)) that enables tumor-specific cGAS-STING activation via catalytic phase separation for targeted immunotherapy in spinal metastasized breast cancer. Specifically, MIL-88B(Fe─O─V) undergoes disassembly within the acidic TME to release iron ions and polyoxovanadate (POV). Iron ions enable catalytic reactive oxygen species (ROS) generation to release double-stranded DNA (dsDNA) and induce immunogenic cell death (ICD). Critically, we demonstrate for the first time that POV potently promotes liquid-liquid phase separation (LLPS) of cGAS, enhancing its affinity for dsDNA and amplifying STING pathway activation in dendritic cells (DCs) without systemic immune dysregulation. Such combinational ICD induction and LLPS-driven cGAS activation synergistically boost DC maturation, cytotoxic T-cell responses, and establish durable antitumor immunity. In spinal metastasis models, MIL-88B(Fe─O─V) not only achieves robust tumor regression and prolonged survival, but also mitigates cancer-related pain via IFN-β-mediated suppression of TRPV1 channel activity. Our findings unveil a paradigm of nanocatalytic STING activation for advanced metastatic cancer metalloimmunotherapy and cancer pain alleviation.

Insufficient T-cell infiltration is a major barrier to the efficacy of immune checkpoint inhibitors (ICIs) in lung adenocarcinoma (LUAD). We aimed to investigate how the tumor-intrinsic m5C methyltransferase NSUN2 shapes the immune landscape of LUAD. Nsun2 conditional knockout mice and syngeneic mice models were employed. Single-cell RNA sequencing (scRNA-seq) and m5C sequencing were performed to elucidate the downstream pathway regulated by NSUN2. LUAD specimens from patients receiving neoadjuvant immunotherapy were used to assess the correlation between NSUN2 expression and immune infiltration. Elevated tumoral NSUN2 expression was correlated with a marked lack of CD8+ T-cell infiltration and immunotherapy resistance. Mechanistically, NSUN2 enhances the translation of histone deacetylase HDAC8 in an m⁵C-YBX1-dependent manner, which in turn directly represses the transcription of the chemoattractant CCL5, thereby impairing CD8+ T-cell recruitment into the tumor. NSUN2 depletion reversed this immunosuppressive axis and converted immunologically "cold" tumors into "hot". Tumor-targeted liposomes loaded with the NSUN2 inhibitor synergized with anti-PD-1 therapy to induce significant tumor regression. Our findings identify NSUN2 as a critical orchestrator of T-cell exclusion in LUAD. It serves as both a candidate predictive biomarker for ICI failure and a promising druggable target. Targeting NSUN2 offers a potential strategy to overcome immunotherapy resistance and improve clinical outcomes in LUAD patients.

Chondrosarcoma remains refractory to immunotherapy due to a paucity of targetable antigens and a suppressive tumor microenvironment (TME). We developed a modular strategy integrating tumor-intrinsic genetic logic with rational TME reprogramming to overcome these barriers. Using a 57,715-element massively parallel reporter assay, we identified chondrosarcoma-selective synthetic promoters and engineered a Boolean AND-gate circuit that ensures high-fidelity expression of a surface T cell engager exclusively within malignant cells. To further address the immunosuppressive TME, we identified macrophage migration inhibitory factor (MIF) as a target for blockade. Single-cell RNA sequencing in human PBMC-reconstituted chondrosarcoma xenograft models revealed that the circuit initiates T cell activation, while MIF blockade prevents exhaustion by promoting proliferative T cells and M1-polarized macrophages. Local administration induced a systemic abscopal effect, regressing distant, untreated tumors. Collectively, these findings provide a programmable blueprint for converting immunologically cold, antigen-poor malignancies into systemically immune-responsive states.

Brain tumors are the most common solid tumors in children. Despite recent advancements in cancer survival, the prognosis for high-grade pediatric brain tumors remains poor, with treatments resulting in severe long-term side effects. Over the last decade, immune checkpoint blockade (ICB) has emerged as a promising treatment strategy, with success across various tumor types, particularly in adult malignancies. However, its efficacy in pediatric brain tumors has been limited, which can be attributed to the unique characteristics of the brain tumor microenvironment (TME), including a low mutational burden, restricted T cell infiltration, and immunosuppressive milieu. Importantly, clinically approved ICBs primarily target T cell-associated pathways, thereby neglecting other dominant immune populations within the TME.Among these, tumor-associated macrophages (TAMs) often represent the most abundant immune cell compartment within pediatric brain tumors. TAMs consist of resident microglia and infiltrating bone marrow-derived macrophages and play a central role in establishing and maintaining an immunosuppressive environment. They promote tumor progression, suppress cytotoxic T cell activity, and contribute to therapeutic resistance. However, they are highly heterogeneous, and their phenotype and functions are regulated by the surrounding TME. This intrinsic plasticity makes them promising therapeutic targets: rather than solely attempting to enhance T cell activity, reprogramming TAMs may fundamentally remodel the immune landscape of pediatric brain tumors.In this context, immune inhibitory receptors emerge as critical regulators of TAM function. While traditionally studied in T cells, inhibitory receptors expressed on macrophages influence phagocytosis, cytokine production, antigen presentation, and polarization states. Emerging preclinical evidence indicates that targeting inhibitory receptors on TAMs can shift macrophages from suppressive toward pro-inflammatory phenotypes, enhance phagocytosis, and improve survival in brain tumor models. Nevertheless, the expression patterns and functional consequences of these receptors in pediatric brain TAMs remain incompletely characterized.In this review, we examine the role of immune inhibitory receptors on TAMs in pediatric brain tumors and discuss how targeting these pathways may reprogram the TME, enhance antitumor immunity, and provide new therapeutic avenues for this challenging group of malignancies. Unlike most pediatric brain tumor immunotherapy reviews, this review specifically evaluates myeloid-targeted inhibitory receptor pathways in the pediatric brain tumor context.

Oncolytic virus M1 encoding a mutant IL-18 decoy (OVM18) represents a novel virotherapy that integrates selective oncolysis with localized activation of the IL-18 pathway. However, the heterogeneity of therapeutic responses suggests that host immune determinants influence its efficacy. To elucidate these determinants, we performed integrated immune profiling using bulk and single-cell transcriptomics, flow cytometry, and T cell receptor (TCR) repertoire analyses. The functional contribution of specific immune subsets was validated using Batf3⁻/⁻ mice and FTY720-mediated lymphocyte trafficking blockade. Potential synergistic immunotherapies were identified through transcriptomic database screening and confirmed in tumor-bearing mice receiving combined OVM18 and immune checkpoint blockade. We identified intratumoral IL-18R1+CD8+ T cells as an important effector population, whose IL-18R1 expression and intratumoral abundance positively correlate with OVM18 efficacy. Integrated single-cell RNA-sequencing and cytometry analyses revealed that IL-18R1+CD8+ T cells are clonally expanded, tumor antigen-enriched, polyfunctional cytotoxic T cells. Their generation requires conventional type 1 dendritic cells (cDC1)-dependent priming within tumor-draining lymph nodes, followed by trafficking into tumors to mediate antitumor responses. Notably, CTLA-4 blockade enhances cDC1-derived IL-12 and promotes IL-18R1+CD8+ T-cell expansion, thereby overcoming resistance to OVM18 therapy. Combination treatment with OVM18 and anti-CTLA-4 enhances intratumoral IL-18R1+CD8+ T cell infiltration, delays tumor progression, and prolongs survival in poor-responsive models. Our findings establish IL-18R1+CD8+ T cells as an important effector population in OVM18 therapy, thereby providing a strong rationale for combining OVM18 with CTLA-4 blockade to overcome therapeutic resistance and achieve durable antitumor responses.

Despite the transformative advances that have been made in cancer immunotherapy, primary and acquired resistance remain prevalent, limiting durable clinical benefits. Mechanistic studies on immunotherapeutic resistance have largely focused on genetic, transcriptional, signaling, and metabolic programs within tumor and immune cells, with organelle physical routes and metabolic exchange across the tumor-host interface remaining relatively underexplored. Tunneling nanotubes (TNTs), membranous conduits that mediate long-range intercellular exchange, are increasingly implicated in tumor microenvironment remodeling. Thus, TNT-mediated mitochondrial transfer may represent an underexplored intercellular communication axis that can potentially influence tumor adaptation and immunotherapeutic responses. By enabling tumor cells to acquire functional mitochondria from neighboring stromal or immune cells, TNT-associated transfer may reinforce oxidative metabolism, redox homeostasis, and survival under immune and therapeutic pressure. Conversely, although the functional consequences of mitochondrial exchange are strongly dependent on the donor-recipient context, the transfer of tumor-derived mitochondria may result in the reprogramming of recipient immune or stromal cells and favor immunosuppressive states. However, direct evidence establishing TNT-mediated mitochondrial transfer as a causal determinant of immunotherapeutic resistance remains limited and varies significantly across therapeutic modalities. This review discusses the molecular mechanisms governing TNT formation and mitochondrial trafficking, examines the metabolic and immunological consequences of bidirectional tumor-host mitochondrial exchange, critically evaluates evidence linking these processes to distinct immunotherapeutic modalities, and discusses strategies and experimental priorities for their therapeutic translation.

First-line treatment for gastric cancer (GC) includes PD-1 blockade with chemotherapy, but resistance challenges treatment success. We identify Streptococcus anginosus (SA) as a tumor-resident oncobacterium driving GC progression and immune evasion. SA is enriched in GC patient tumors and drives tumor growth in mice. SA extracellular vesicles (saEVs) translocate the bacterial chromatin remodeler saSNF2 into host cells. saSNF2 partners with host transcription factor TEAD1-through its ATPase activity and participation in BRG1/BRM-associated factor (BAF) complex assembly-to activate oncogenic transcription. This transkingdom interaction upregulates the palmitoyltransferase ZDHHC11, which stabilizes PD-L1 via palmitoylation to establish an immunosuppressive niche, while amplifying other TEAD1 target genes to fuel tumor progression. saEVs promote tumor growth and limit CD8+ T cell infiltration in vivo. Pharmacological inhibition of ZDHHC11 reverses immune evasion and synergizes with anti-PD-1 checkpoint blockade. These findings establish SA as a multifaceted driver of GC and highlight the saSNF2-ZDHHC11 axis as a target to potentiate immunotherapy.

Precision oncology faces three systemic bottlenecks: static molecular snapshots fail to capture tumor dynamics, patient‑derived organoids lack physiological reconstruction of the tumor microenvironment (TME), and artificial intelligence (AI) remains a "black box" in clinical decision‑making. This review aims to propose an integrated closed‑loop framework that addresses these challenges by combining dynamic multi‑omics monitoring, next‑generation bioengineered models, and explainable AI. This review synthesizes recent advances in microfluidics, organoid technology, CRISPR screening, and multimodal data integration and, more importantly, proposes a closed-loop framework that distinguishes itself from existing approaches by explicitly linking dynamic monitoring, functional organoid testing, and explainable AI into an iterative decision cycle. Liquid biopsy enables longitudinal tracking of tumor evolution, while vascularized organoids and organ‑on‑chip systems reconstruct key TME features such as oxygen gradients, shear stress, and immune‑stromal interactions. These models serve as "therapeutic sandboxes" for functional drug testing and resistance mechanism elucidation. Concurrently, explainable AI (XAI) techniques-including feature perturbation, knowledge graph embedding, and dynamic Bayesian networks-provide interpretable predictions of treatment response. We outline a closed‑loop paradigm where dynamic monitoring data inform organoid‑based assays, XAI translates experimental evidence into clinical decisions, and real‑world outcomes continuously refine the models. Technical challenges such as multi‑scale data integration, vascularization fidelity, and AI transparency are discussed, along with emerging solutions including federated learning, 3D bioprinting, and standardized quality control pathways. Integrating dynamic monitoring, physiologically relevant organoid models, and explainable AI establishes a convergent precision oncology ecosystem that shifts the field from static biopsy‑based decisions toward adaptive, closed‑loop personalized therapy. This paradigm holds promise for overcoming tumor heterogeneity, predicting drug resistance, and improving clinical outcomes, while also providing a roadmap for future translational research and regulatory harmonization.

Cancer neuroscience has expanded the conceptual landscape of tumor biology by revealing that nerves are not passive bystanders within malignant tissues, but active regulators of tumor progression, immune surveillance, and therapeutic response. Among neural components of the tumor microenvironment, nociceptive sensory neurons have emerged as critical interfaces between tissue injury, inflammation, cancer-associated pain, and immune regulation. This review proposes that nociceptive neuron-driven immune escape represents a tissue-level pathological process positioned at the intersection of cancer neuroscience, tumor immunology, and immunometabolism. We discuss how tumor-associated inflammatory mediators, extracellular acidosis, mechanical stress, metabolic perturbations, and axon-guidance programs activate nociceptors and induce the release of calcitonin gene-related peptide (CGRP) and related neuropeptides. Through receptor activity-modifying protein 1-containing receptor complexes, CGRP can suppress CD8⁺ T-cell receptor signaling, promote exhaustion-associated transcriptional and metabolic programs, impair dendritic cell function, and reinforce suppressive myeloid and regulatory immune compartments. We further examine how tumor cells may co-opt the ATF4-SLIT2-CGRP axis to establish cross-organ neuroimmune circuits extending to tumor-draining lymph nodes, thereby weakening antigen presentation, T-cell priming, and responsiveness to immune checkpoint blockade. Finally, we consider lactate accumulation and extracellular acidification as parallel immunometabolic pressures that may consolidate nociceptor-associated immune dysfunction by constraining T-cell bioenergetic fitness, promoting suppressive immune states, and potentially modulating sensory-neuron activity. Rather than defining a fixed linear pathway, we conceptualize the nociceptor-CGRP-lactate axis as an integrative neuroimmune-metabolic framework in which partially independent neural and metabolic processes converge on shared mechanisms of immune escape. This framework provides a translational rationale for evaluating combined neural, metabolic, and immune checkpoint-directed interventions in cancers characterized by neural involvement, metabolic suppression, and immunotherapy resistance.

To summarise the literature regarding the safety of short-term use of the non-steroidal anti-inflammatory drug (NSAID) celecoxib. Systematic review with meta-analysis of randomised trials. Participants comprised individuals of all ages with acute non-cancer pain. Interventions included celecoxib at 200-400 mg/day for up to 10 days. The comparators were placebo, other NSAIDs (including cyclooxygenase-2 [COX-2] inhibitors and non-selective NSAIDS [nsNSAIDS]), or opioids. Five databases were searched from inception to April 2025: Embase, Web of Science, MEDLINE, Cochrane Central Register of Controlled Trials, and Scopus. Additionally, a registry was searched: ClinicalTrials.gov. Meta-analyses using Mantel-Haenszel and random-effects model were used to calculate risk ratios (RRs) and 95% confidence intervals (CIs) for severe cardiovascular, respiratory, and gastrointestinal adverse events and secondary outcomes. The Cochrane Risk of Bias Tool for randomised trials (RoB-2) was used to assess bias risk. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) was conducted to assess the certainty of evidence of each reported outcome. Title/abstract and full text screening comprised 3976 and 273 studies, respectively. Fifty studies were included with 10,693 participants. The RRs for adverse events were no different between celecoxib and placebo for severe events (3 studies) (RR 0.44 [95% CI 0.10-2.03]), cardiovascular (3 studies) (RR 0.84 [95% CI 0.24-2.92]), respiratory (4 studies) (RR 1.23 [95% CI 0.29-5.26]), and gastrointestinal events (33 studies) (RR 0.96 [95% CI 0.64-1.43]). There was no difference between celecoxib and NSAIDS for gastrointestinal adverse events, RR 0.89 (95% CI 0.68-1.17). Celecoxib had a lower risk compared to opioids for gastrointestinal events, RR 0.34 (95% CI 0.14-0.86), and showed a lower risk of nausea compared with placebo, RR 0.75 (95% CI 0.60-0.93), and nsNSAIDS, RR 0.80 (95% CI 0.64-0.99). Most studies had some risk of bias concerns, and the overall certainty of evidence for most outcomes was very low. Celecoxib appears to be safe for acute non-cancer pain when compared to placebo, NSAIDS, and opioids. It had a lower risk compared to opioids for gastrointestinal adverse events in general, nausea and vomiting, as well as a lower risk for nausea adverse events when compared to placebo and nsNSAIDS. PROSPERO-CRD42025642152.

Aging epithelial tissues, including the esophagus, are colonized by somatic mutant clones under strong competitive selection. The effect of cancer treatment on mutant selection in normal epithelium is unknown. We hypothesized that some mutant clones may be selectively expanded during treatment. To test this, we sequenced normal esophageal epithelium removed from 70 patients after therapy for esophageal cancer. Patients received either no treatment, combination chemotherapy (FLOT, ECX or EOX) or chemotherapy and radiation therapy (CROSS). Mutant TP53 and PPM1D clones were expanded in patients undergoing CROSS. In the group undergoing FLOT, there was increased selection for RAC1, NFE2L2 and MTOR mutations consistent with these mutants conferring 5-fluorouracil resilience in normal epithelium. Sequencing normal epithelia reveals treatment-specific selection of mutations and may identify genes implicated in cellular responses to therapy.

MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers. We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits. About 12 000 CRC and multiple polyp cases and 460 000 controls were studied. 2023 patients underwent cancer genome sequencing. One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (2.2-fold, p=6.6×10-5 and 1.6-fold, p=0.028, respectively), owing to somatic 'second hits' that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable but hypermutant. Deletions of ≥2 bp were particularly increased (~12-fold) and signature ID4 was usually present (p<0.0001). CRCs from heterozygotes without 'second hits' showed no hypermutation. The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some patients with cMMRd. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2-mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency.

Platinum and taxanes are backbone chemotherapy in multiple solid tumours. We aimed to investigate the safety, tolerability, and pharmacokinetics of nab-paclitaxel and cisplatin administered by pressurised intraperitoneal aerosol chemotherapy (PIPAC). Nab-PIPAC is a phase 1b trial investigating PIPAC administration of cisplatin at 10.5 mg/m2 and escalating dose of nab-paclitaxel with a 3 + 3 design (7.5, 15, 25, 37.5, 52.5 and 70 mg/m2). PIPAC was repeated at 4-6 weeks intervals for up to three courses to estimate the maximum tolerated dose (MTD). We enrolled 22 patients with peritoneal carcinomatosis, of whom 18 received at least one PIPAC: 6 ovarian, 9 gastric and 3 pancreatic cancers. Four patients (ovarian cancer) did not receive PIPAC due to bowel obstruction (n = 1) or no access to peritoneal cavity (n = 3). Median age was 67 years (43-81). In total, 45 PIPAC procedures were administered and 12 of 18 (67%) patients completed three PIPAC cycles. There was no dose limiting toxicity. The most common side effect was abdominal pain. One patient had grade 3 treatment related adverse event: bladder lesion requiring surgical reintervention. Median progression-free survival was 3.5 months and median overall survival was 9.4 months. Five patients with gastrointestinal cancer survived more than one year (3 gastric and 2 pancreatic). Pharmacokinetic analyses showed good linearity between nab-paclitaxel dose and the AUC0-last (R2 = 0.90). The combination of nab-paclitaxel and cisplatin administered by PIPAC was safe and well tolerated in patients with peritoneal carcinomatosis. Further investigation of this combination is warranted. The study was supported by la bourse jeune chercheur des Hopitaux Universitaires de Geneve (NL), Fondation Fond'action (ILG) and Fondation NOVA (ILG).

The human microbiome is spatially compartmentalized, yet oral bacteria can ectopically colonize distal sites such as the gut, potentially influencing disease. By analyzing paired oral and fecal microbiomes from 507 participants across healthy controls and patients with metabolic disorders or gastrointestinal cancers, we established a quantitative mouth-to-feces (MF) index to measure MF microbial transmission. The MF index revealed elevated mouth-to-gut transmission in cancer and a strong association with host metabolic and inflammatory indicators. Using transmitted taxa, we developed a random forest classifier that accurately distinguished gastric/colorectal cancer from healthy controls across seven independent cohorts, even when trained solely on oral microbiome data. When benchmarked against the conventional screening test, the MF-based model achieved markedly higher sensitivity than the fecal occult blood test. These findings uncover disease-specific transmission signatures and highlight MF microbial profiling as a generalizable, non-invasive framework for gastrointestinal cancer diagnosis and risk stratification.

To investigate associations between walking speed (WS) and mortality among patients with stable cardiovascular disease (CVD). Additionally, it sought to analyse the impact of a long-term exercise intervention on physical function by analysing the relationship between changes in WS and mortality over a decade of observation. Of the 3328 patients included in the ITER registry (NCT05817305) between 1997 and 2023, 2858 (aged 65 ± 11 years) were analysed. Walking speed was measured using the 1-km treadmill walking test (1k-TWT). Patients were initially categorized into tertiles based on baseline WS and subsequently divided into six categories by associating baseline WS with changes over time. Cox proportional hazard models were used to examine associations between WS, all-cause and disease-specific mortality, adjusting for demographic and clinical confounders. A total of 1031 patients died over a median follow-up of 11 years. Higher baseline WS was inversely associated with mortality with magnitudes ranging from 23% (95% CI: 0.56, 1.06) lower risk for cancer to 58% (95% CI: 0.32, 0.54) lower risk for CVD. A similar trend resulted in WS improvements over time, particularly among the LowWS-improved group, with a 38% (95% CI: 0.52, 0.74) lower risk for all-cause mortality, which was comparable to the HighWS-decreased patients. The 1k-TWT is an effective predictor of mortality among CVD patients and a valuable educational tool for exercise-based interventions in secondary prevention. These findings highlight the efficacy of exercise-based programs to improve physical function and reduce mortality, underscoring the importance of promoting exercise as part of long-term CVD management.

Advances in colorectal cancer (CRC) screening and endoscopic techniques have led to increased detection of T1 CRC. Patient management relies on histopathological criteria predicting lymph node metastasis (LNM), including submucosal invasion depth (SID) >1000 µm. However, the independent prognostic value of isolated deep invasion remains unclear. We performed a retrospective multicenter study of patients treated at 18 European centers between 2009 and 2022. Patients with T1 CRC endoscopically resected en bloc and with isolated SID >1000 µm (without other high-risk features) were included. Two groups were analyzed: patients who underwent additional surgery and those who were followed with surveillance. Rates of LNM (surgery group) and recurrence (local and distant; surveillance group) were assessed. Exploratory multivariable analyses were performed to evaluate clinicopathological factors associated with LNM. Among 179 included patients (124 surgery, 55 surveillance), LNM was found in 16/124 surgical specimens (12.9%; 95%CI 7.7-20.4) and recurrence occurred in 2/55 patients undergoing surveillance (3.6%; 95%CI 0.4-12.6). LNM occurred in 1/50 patients (2.0%) with SID <2000 µm and in 15/74 patients (20.3%) with SID ≥2000 µm. Multivariable analysis revealed SID ≥2000 µm (odds ratio [OR] 3.59; 95%CI 1.14-13.71) and colonic (vs. rectal) tumor location (OR 3.63; 95%CI 1.07-16.77) as factors associated with LNM. Isolated deep submucosal invasion in T1 CRC was associated with a non-negligible rate of LNM in this real-world cohort. In exploratory analyses, SID ≥2000 µm was associated with LNM.

Lipocalin 2 (LCN2) is upregulated in many cancers, including pancreatic ductal adenocarcinoma (PDAC), and contributes to tumor development. LCN2 regulates microbial composition, which can influence PDAC outcomes, and has been implicated in ferroptosis resistance in several cancer types. However, the role of tumor-derived LCN2 in mediating ferroptosis and the tumor microbiome in PDAC remains unclear. Here, we show that human PDAC tumors with high LCN2 expression have altered expression of genes involved in ferroptosis, oxidative stress responses, and microbial regulation. Loss of LCN2 in PDAC cells dysregulates ferroptosis-associated pathways, increases lipid peroxidation, and sensitizes cells to ferroptosis induction. In orthotopic PDAC models, the ferroptosis inducer imidazole ketone erastin (IKE) promoted tumor growth in Lcn2-expressing tumors, whereas this effect was absent in tumors lacking LCN2. In addition, tumor-derived Lcn2 expression and ferroptosis induction were associated with distinct changes in the pancreatic tumor microbiome. Overall, these findings identify tumor-derived LCN2 as an important modulator of ferroptotic stress responses in PDAC and suggest that inhibition of tumor-derived LCN2 may enhance susceptibility to ferroptosis-based therapeutic strategies.

Changes of three-dimensional chromosome organization in cancers are well established, but little focus has been placed on the behaviour of X chromosome (chrX). Here we show that hepatic chrX of male mice exhibits chromosome segregation, which is attenuated during hepatocellular carcinoma (HCC) development. Using F1 hybrid mice, we find that both conformation change and gene activation on male active chrX (Xa) are more pronounced than those on female Xa, which is correlated with male bias in liver diseases. Of note, analysis of human hepatic tissues demonstrates that normal Xa possesses a bipartite mega-domain structure, which is dissolved in fibrotic and HCC tissues across both sexes. This bipartite Xa is liver-specific, and shows little correlation with ploidy status. Furthermore, deletion of the megabase-scale Xa boundary via CRISPR-Cas3 disrupts the bipartite Xa conformation and drives a premalignant transition. Together, this comprehensive analysis highlights a key role of Xa conformation change in promoting HCC development.

Anaphylatoxins are active complement components that regulate immune cells. However, their role in shaping the tumor immune microenvironment (TIME) in hepatocellular carcinoma (HCC) remains poorly understood. This study utilized CRISPR/Cas9 technology to knock out complements proteins C3 or C5 in mouse liver cancer cells. Both in vivo and in vitro experiments revealed that C5 knockout significantly inhibited tumor growth in mouse models. Moreover, C5ar1-knockout mice were generated using C57BL/6J mice, and immune cell profiles within subcutaneous tumors were analyzed using mass spectrometry and flow cytometry. The results demonstrated that C5ar1 knockout significantly reduced the infiltration of regulatory T cells (Tregs) and M2-like tumor-associated macrophages (TAMs) into the TIME. Conversely, the infiltration of effector CD8+ T cells, known for their tumor-killing activity, was markedly enhanced. Mechanistically, C5a was shown to promote the M2-like polarization of macrophages and the C-C-motif chemokine ligand 5 (CCL5) expression by activating the AKT signaling pathway. Further studies identified TAM-derived CCL5 as a key driver of the chemotactic activity of Tregs. Finally, blocking the C5a/C5ar1 axis synergistically enhanced the anti-tumor effects of PD-1 monoclonal antibody in both transplanted and spontaneous liver cancer mouse models. Overall, these findings reveal that cancer cell-derived anaphylatoxin C5a plays a pivotal role in promoting an inhibitory TIME in liver tumor tissues. Blocking the C5a/C5ar1 axis in combination with immune checkpoint inhibitors could represent a promising strategy for treating HCC.

Hepatocellular carcinoma (HCC) originates from premalignant disease-associated hepatocytes (daHeps) that emerge during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH). As daHeps are compensatorily primed by metabolic stress, we reproduced the accelerated progression of MASLD-associated HCC in mice by phenocopying the decreased expression of a metabolic regulator, protein arginine methyltransferase 1 (PRMT1). In Prmt1 liver-specific knockout (LKO), m6A-mediated changes in mRNA stability reprogram the transcriptome via paralog compensation; increased PRMT6 activates m6A methyltransferases by inducing asymmetric arginine dimethylation of METTL3. This event enhances global m6A deposition that leads to the down-regulation of Keap1, which would trigger the NRF2 axis, promoting premalignancy; under diet- and chemical-induced stress, the incidence of steatohepatitic HCC was increased, clinically correlating with the PRMT-METTL3-NRF2 pathway. Together, we propose that compensatory arginine methylation primes MASLD-associated HCC by modulating m6A-mediated transcriptome and NRF2 regulatory pathways as adaptive defenses against metabolic and oxidative stress.

Combining glucose oxidase (GOx) with peroxidase-like (POD) nanozymes is a well-established strategy for synergistic starvation and chemodynamic therapy (CDT). However, the low catalytic efficacy of most nanozymes compared to GOx often leads to wasteful accumulation of hydrogen peroxide (H2O2), which can inhibit GOx activity and limit the therapeutic effect. Therefore, enhancing the H2O2 consumption efficiency is critical to unlocking the full potential of this approach. Here, we designed a cobalt-doped mixed-valence copper oxide (Co-CuxO) nanozyme with metals uniformly dispersed using a polyacrylic acid (PAA) scaffolding method. This nanozyme tightly couples the redox cycles that drive the valence state interconversions of cobalt (Co) and copper (Cu) elements, enabling highly efficient consumption of H2O2 and glutathione (GSH). While Co provides multi-valent characteristics ideal for Fenton-like reactions, Cu acts not only as a co-catalyst but also triggers cuproptosis. We further installed GOx onto the nanozyme surface, allowing H2O2 produced by GOx channels to Co-CuxO active sites, thereby further accelerating the catalytic cascade. In vitro experiments demonstrated effective glucose and H2O2 depletion with abundant hydroxyl radical (·OH) generation. When functionalized with hyaluronic acid (HA) for tumor targeting, in vivo experiments demonstrated robust multimodal cell death, confirming the high efficacy of our integrated dual-enzyme platform.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a major global health burden, bridging isolated steatosis, progressive fibrosis and hepatocellular carcinoma. Recent paradigms highlight ferroptosis, an iron-dependent, lipid-peroxidation-driven form of regulated cell death, as a primary lytic initiating event in metabolic liver injury. In this review, we delineate the ferroptosis-immune axis in MASH, characterising it as a self-amplifying, bidirectional circuit. In this framework, parenchymal ferroptotic rupture and damage-associated molecular pattern emission drive myeloid activation and pro-inflammatory cytokine release. This inflammatory microenvironment reciprocally triggers cell-autonomous Kupffer cell ferroptosis and homeostatic collapse. We establish a novel cell-type-specific transcriptomic framework governed by a core four-gene signature (FABP4, CAPG, QSOX1 and FXN) that maps the transition from early metabolic stress to advanced structural remodelling. Furthermore, we decode the substrate paradox of polyunsaturated fatty acids, illustrating how their role shifts from physiological signalling to executioner substrates when antioxidant systems collapse. This biophysical vulnerability is heavily primed by inherited gene polymorphisms, including PNPLA3, TM6SF2 and MBOAT7 By evaluating the sexual dimorphism embedded within these pathways, specifically how the DTL-PROX1 axis dictates distinct iron accumulation rates and lipid peroxidation sensitivities, we propose precise clinical stratification strategies. Finally, we outline actionable translational avenues, highlighting how targeting the ferroptosis-immune axis offers a highly specific therapeutic window to arrest lipotoxicity, suppress inflammation and disrupt oncogenic priming before irreversible tissue remodelling occurs.

Gemcitabine resistance remains a major challenge in the treatment of gallbladder cancer (GBC). Here, we elucidate a novel mechanism underlying gemcitabine resistance in GBC, centered on a self-reinforcing mitophagy/ROS/SENP3/Reptin loop. Gemcitabine-resistant GBC cells maintain significantly lower intracellular reactive oxygen species (ROS) levels than wild-type cells through enhanced mitophagy. This finding delineates a novel transcriptional mechanism that drives mitophagy under low ROS conditions. Mechanistically, this low ROS state decreases the protein abundance of the ROS sensor Sentrin/SUMO-specific protease 3 (SENP3), thereby promoting SUMOylation of its substrate, RuvB-like AAA+ ATPase 2 (Reptin), at the K456 site. SUMOylated Reptin translocates to the nucleus, where it acts as a transcriptional activator to specifically upregulate PTEN-induced putative kinase 1 (PINK1), a key mitophagy regulator. Enhanced PINK1 expression further amplifies mitophagy, effectively scavenging ROS and perpetuating the low ROS state that drives resistance, thus sustaining the gemcitabine-resistant phenotype. Clinically, low SENP3 expression and high Reptin expression correlate with poor gemcitabine response and shorter overall survival in GBC patients. Targeting this pathway, the Reptin ATPase inhibitor CB-6644 effectively suppressed PINK1 transcription, inhibited mitophagy, increased ROS accumulation, and reversed gemcitabine resistance both in vitro and in vivo. These findings identify the mitophagy/ROS/SENP3/Reptin loop as a core resistance mechanism in GBC, highlight SENP3 and Reptin as predictive biomarkers, and establish CB-6644 as a promising therapeutic agent to overcome gemcitabine resistance by disrupting this adaptive pathway.

SUMMARYColorectal cancer (CRC) is a significant global health concern that is growing in prevalence, especially in younger populations. The gut microbiome is an increasingly recognized factor in the development and progression of numerous diseases, including CRC. This review explores the current research on the causal relationship between the microbiome and CRC, including the strengths and limitations of the current models for studying this complex interaction. We then delve into key microbial metabolites and their effects on host signaling pathways in the context of CRC and highlight specific bacterial species with direct links to CRC development and progression. Existing microbiota-targeted therapies such as pre- and pro-biotics and fecal microbiota transplantation are described, as well as innovative microbiome-focused strategies that are currently in development, like quorum quenching. Finally, we address the major challenges in the field, such as conflicting research findings and the need for a systems-level, multi-omic approach to describe the intertwined and bidirectional host-microbe interactions.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by hepatic steatosis, inflammation, and fibrosis, which can ultimately lead to cirrhosis and hepatocellular carcinoma. Although recent Food and Drug Administration approvals of resmetirom and semaglutide mark a milestone in MASH therapy, no approved agents directly target hepatic inflammation or fibrosis, underscoring the urgent need for novel therapeutic strategies. Hepatocyte death is a histological hallmark that distinguishes MASH from simple steatosis, yet the mechanisms by which it drives chronic inflammation and fibrosis remain incompletely understood. We identified hepatic crown-like structures (CLSs), aggregates of macrophages surrounding dead hepatocytes, as the histological hub of this process. In steatotic livers, impaired dead cell clearance allows sustained macrophage-dead cell interactions within CLSs, where tissue-resident macrophages acquire profibrotic properties. Cholesterol accumulation in hepatocytes promotes cholesterol crystallization, triggering hepatocyte death and subsequent lysosomal cholesterol overload in CLS-constituting macrophages, thereby accelerating inflammation and fibrosis. Targeting this pathway using a liver-tropic supramolecular β-cyclodextrin polyrotaxane (βCD-PRX), which selectively delivers βCD to lysosomes via endocytosis, ameliorated macrophage lysosomal stress and hepatic fibrosis in murine MASH models without affecting body weight or steatosis. Beyond the liver, CLS-driven chronic inflammation contributes to adipose tissue dysfunction in obesity and the transition from acute kidney injury to chronic kidney disease, suggesting broad therapeutic relevance. Continued investigation of CLSs as a shared pathological microenvironment across metabolic diseases may pave the way for novel diagnostic and therapeutic modalities for MASH and related conditions.

Protein-drug conjugates (PDCs) constitute a rapidly growing group of precise anticancer agents. Receptor-mediated endocytosis is a critical step in PDC action, which ensures the delivery of PDCs into the interior of cancer cells. Here, we report TriFHS-MMAE, the first multivalent PDC specifically targeting heparan sulfate proteoglycans (HSPGs) overexpressed by pancreatic cancer cells, which induces ultrafast and highly efficient aggregation-dependent endocytosis (ADE) of HSPGs. Using high-content screening with a near-kinome-wide library of inhibitors, we identified signaling pathways that govern ADE of HSPGs and discovered cascades that selectively operate in pancreatic cancer cells versus healthy cells. We show that priming cells with identified endocytic chemical modulators improves the targeting of the TriFHS-MMAE conjugate in vitro and in vivo. Overall, these findings provide insights into the interplay among signaling, endocytosis, and PDCs and support the development of specific therapies for pancreatic cancer.

Integrating localized amino acid perturbation with systemic metabolic regulation represents a compelling strategy to exploit tumor metabolic vulnerabilities. However, current metabolic modulators remain challenged by poor tumor selectivity, limited oral bioavailability, and reliance on complex delivery systems that hinder clinical translation. Here, we report a fasting-augmented amino acid intervention strategy using iron-cystine spherulites (FeCST). Following oral administration, FeCST is converted in the stomach into ultrasmall cystine nanoparticles (FeCST-NPs) that traverse intestinal mucus and enter systemic circulation via the paracellular pathway. In the bloodstream, FeCST-NPs spontaneously reassemble with specific plasma proteins into nanoclusters, which may contribute to their preferential accumulation in tumors. Synergistically, FeCST and intermittent fasting (IF) robustly induce disulfidptosis, resulting in potent tumor suppression and enhanced antitumor immunity. This synergistic effect is associated with multiple IF-induced metabolic alterations, including glucose restriction and transient modulation of intestinal epithelial permeability, which collectively facilitate FeCST bioavailability and increase tumor susceptibility to disulfide stress. This study presents a disulfidptosis-mediated paradigm that integrates controlled amino acid intervention with fasting-mediated systemic metabolic modulation.

Pancreatic cancer faces the challenges of tumor progression and postoperative pancreatic fistula during the perioperative period, which severely affect patient prognosis. In this study, an injectable self-healing multifunctional hydrogel (CMCGel) was developed based on dynamic cross‑linking between manganese ions (Mn2+) and carboxymethyl chitosan loaded with chlorella extract (CE). This platform implements an integrated "Remove-Remodel-Repair" (3R) strategy for comprehensive perioperative management. CMCGel exhibits distinctive pH/laser dual-responsive behavior: In the acidic tumor microenvironment, the accelerated release of CE and Mn2+ enhances photodynamic therapy and chemodynamic therapy (CDT). This combination, activated by laser and gated by endogenous pH, achieves remarkable tumor suppression rates of 85.81% in vitro and 96.01% in vivo. As pH normalizes, Mn2+ shifts from CDT to activate the cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway, remodeling the immune microenvironment. Crucially, CMCGel's adhesion strength in artificial pancreatic fluid at 48 h was 4703.80 ± 50.36 Pa, only 8.17% lower than that at 10 min. This enzyme-resistant property enables durable mechanical sealing at the fistula site, reducing amylase leakage by 55.71% and creating favorable conditions for tissue repair. By integrating pH/laser-triggered combination therapy, immunomodulation, and enzyme-resistant barrier functionality into a single platform, CMCGel presents a clinically promising strategy for perioperative management of pancreatic cancer.

Colorectal cancer (CRC) treatment is severely hindered by the hydrogen sulfide (H2S)-rich microenvironment and metabolic dysregulation, characterized by the Warburg effect and high glutathione (GSH) concentrations. Herein, we engineer a bimetallic phenolic nanoplatform (ZCTDFe, loaded with doxorubicin) to scavenge endogenous H2S and induce metabolic reprogramming, sensitizing tumors to cuproptosis- and ferroptosis-associated processes while integrating photothermal therapy (PTT) and chemotherapy. Through an "etching-coordination" strategy, ZCTDFe effectively scavenged H2S (75.2%) and promoted CuS formation under sulfide-rich cell-free conditions, while intracellular TEM-EDS analysis revealed Cu-S-containing deposits consistent with the scavenging reaction. Seahorse extracellular flux analysis revealed a biphasic bioenergetic response characterized by an early reduction in glycolytic activity accompanied by increased mitochondrial respiratory engagement, followed by later impairment of mitochondrial respiration and glycolytic function. This early respiratory engagement may increase cellular susceptibility to copper-dependent proteotoxic stress involving lipoylated TCA-associated proteins. These metabolic and molecular changes were accompanied by abnormal DLAT oligomerization and loss of Fe-S cluster proteins, supporting the involvement of cuproptosis-associated proteotoxic stress. Meanwhile, the bimetallic center initiates Fenton-like reactions and enhances GSH depletion, thereby weakening the GSH/GPX4 antioxidant defense and promoting ferroptosis-associated lipid peroxidation. Pharmacological rescue experiments supported a synergistic interaction between cuproptosis- and ferroptosis-associated processes within the overall multimodal cytotoxic response. In vitro and in vivo evaluations confirmed its potent antitumor efficacy. The nanoplatform achieved marked tumor growth inhibition in the CRC model without overt systemic toxicity during the short-term observation period.

Fluorescence‑guided surgery using activatable probes is promising, but single‑channel probes often give false negatives-especially in pancreatic cancer due to tumor heterogeneity and limited imaging depth. Here, we built a universal charge-switching gated PET platform based on cyanine dyes bearing a meso-quinolinium moiety. This platform-by decoupling quenching from the recognition group-enabled the construction of two structurally analogous, hypoxia-activatable near-infrared (NIR) probes (Cy5-Ql-NTR and Cy7-Ql-NTR), which have comparable responsive kinetics (sensitive, fast-responding, and low-background), good water solubility and favorable renal clearance, but differ in tissue imaging depth: the former generates brighter signals in superficial regions, while the latter enables deeper tissue penetration and serves as a self-calibration reference. Notably, compared to a single probe, the combined metabolic distribution of the two probes covers a broader range of tumor target tissues. Through their dual-channel imaging, depth-dependent signal attenuation is corrected, and blind spots during probe delivery are reduced. Compared to single-channel fluorescence-guided surgery in subcutaneous pancreatic cancer and orthotopic pancreatic tumor, the dual-channel approach yielded clean margins, preserved significantly more normal tissue, and left no residual tumor on histology. This self-referenced detection strategy suppresses false negatives in single-channel detection, offering a practical and optimized solution for intraoperative guidance in pancreatic cancer.

Peritoneal metastasis is a leading cause of mortality in end-stage gastric cancer and remains poorly responsive to conventional chemotherapy. To address this unmet need, Janus dendron-modified phthalocyanines were developed as tumor-targeted photosensitizers for photodynamic therapy (PDT). A series of Janus dendron-modified phthalocyanines with tailored surface functionalities s synthesized, exhibiting spontaneous self-assembly into nanoparticles with augmented fluorescence, amplified reactive oxygen species (ROS) production, and improved tumor-targeting specificity. Among them, the lead compound TT1-4PYR, bearing pyrrolidone moieties, demonstrated ascites-derived protein corona and macropinocytosis-mediated cellular internalization, enabling deep penetration and selective accumulation in peritoneal metastasis lesions. Comprehensive evaluation in vitro, in vivo, and in human-derived gastric cancer organoid models confirmed its potent and targeted photodynamic cytotoxicity, effectively suppressing tumor progression without inducing systemic toxicity, achieving a favorable biosafety profile. These results highlight TT1-4PYR as a promising and deep-penetrating therapeutic agent for peritoneal metastasis, with potential applicability to other metastatic malignancies.

NAD(P)H is a critical redox cofactor in cellular energy metabolism, yet real-time monitoring of its spatiotemporal dynamics in pathological contexts remains challenging due to the limited penetration depth and resolution of conventional imaging modalities. In this study, we developed a dual-modal ratiometric imaging nanoprobe that enables precise photoacoustic (PA) and upconversion luminescence imaging of this energy metabolism substrates. The nanoprobe conjugates an NAD(P)H-responsive chromophore and an internal reference dye onto NIR-excited upconversion nanoparticles, enabling self-calibrated quantification through ratiometric UCL and mPAT signals. This design minimizes artifacts from nanoprobe distribution and environmental variations, enhancing spatiotemporal accuracy. The utility of the nanoprobe is demonstrated in multiple disease models: it visualizes metabolic reprogramming during macrophage M1 polarization, tracks aberrant NAD(P)H accumulation in drug-induced and acute liver injury (ALI), and monitors metabolic responses to NAC and 2-DG interventions. Furthermore, in a calorie restriction (CR) combined immunotherapy model, the nanoprobe reveals that the TLR7/8 agonist R848 and glycolytic inhibitor 2-DG synergistically suppress tumor growth by reprogramming tumor-associated macrophage metabolism. This work provides a robust imaging platform for tracking energy metabolism dynamics, offering insights into the interplay between metabolic pathways and inflammatory diseases for developing targeted therapies.

As it is a tumour-associated antigen in epithelial cells, research on claudin18.2 (CLDN18.2) has focused on its role as a therapeutic target in pancreatic cancers and its part in maintaining tight junctions. We elucidate the role of trogocytosis-related CLDN18.2 in CD8+ T cells and pancreatic ductal adenocarcinoma (PDAC) progression. We constructed humanised hCD34+, Trp53R172HKrasG12DPdx1-cre (KPC), Cldn18.2 knockout (KO), and patient-derived xenograft/organoid mouse models. Flow cytometry, immunofluorescence, single-cell RNA-sequencing and immunoprecipitation-mass spectrometry (IP-MS) were performed. CLDN18.2+CD8+ T cells indicated poor pancreatic cancer prognosis and immunotherapeutic resistance. CD8+ T cells acquired CLDN18.2 from tumour cells via trogocytosis, inhibiting their activation and cytotoxicity. "Dressed" CLDN18.2 suppressed glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8+ T cells. Mechanically, trogocytosis-related CLDN18.2 induced GSK3β/CK1α-mediated β-catenin phosphorylation, promoting β-catenin ubiquitination and proteasome degradation in CD8+ T cells. CLDN18.2 interacted with β-catenin's N-terminal domain via its C-terminal domain, further strengthening the interaction between β-catenin and CK1α. Moreover, CLDN18.2+CD8+ T cells preferentially 'homed' to the bone marrow through the CXCL12/CXCR4 axis, skewed haematopoietic stem cell myeloid differentiation and induced systemic immune senescence via IL1α. Notably, preclinical mouse studies showed PC18.1 peptide sensitised immunotherapy and suppressed PDAC progression by disrupting the CLDN18.2/β-catenin interaction in CD8+ T cells. Trogocytosis-related CLDN18.2 inhibited the glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8+ T cells by promoting the ubiquitin-proteasomal degradation of β-catenin in PDAC. Therefore, targeting trogocytosis-related CLDN18.2+CD8+ T cells may be a promising therapeutic strategy to inhibit PDAC progression.

Gastric cancer (GC) is one of the most common malignancies worldwide and it is the third leading cause of cancer-related death in China. While Helicobacter pylori is a known GC pathogen, its abundance declines in tumours and the role of other bacteria in GC metastasis remains unclear. We aim to investigate the mechanisms of other bacteria influencing GC progression and metastasis. Integrated intratumoural microbiome-metabolome analysis identified GC-associated microbes and metabolites. We then demonstrated the pro-metastatic role of Acinetobacter baumannii (A. baumannii, Ab) and its metabolite nicotinic acid (NA) using genetic, molecular and in vivo approaches. The abundance of A. baumannii was significantly increased in GC tissues, correlating with advanced tumour stage and intratumoural NA levels. Fluorescence in situ hybridisation confirmed its colonisation in GC tumours. In co-culture systems, A. baumannii increased NA levels, enhancing nicotinamide adenine dinucleotide (NAD) metabolism and increasing 1-Methylnicotinamide accumulation in tumour cells. Mutagenesis of the bacterial NA synthase gene pncA confirmed that A. baumannii excreted an NA-dependent pro-metastasis effect. Mechanically, A. baumannii promotes GC metastasis by reprogramming tumour cell glucose metabolism, reducing oxidative phosphorylation while enhancing glycolysis and activating the hypoxia-inducible factor-1 pathway in GC cells through metabolites both in vivo and in vitro. This study elucidates the role of A. baumannii in enhancing NAD metabolism in GC cells through NA synthesis, consequently promoting GC metastasis. These findings establish a microbiota-metabolism axis as a mechanistic foundation for developing targeted therapeutic strategies against GC metastasis.

Anbenitamab (Ennituo®), a bispecific IgG monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), is being developed by Alphamab Oncology for the treatment of various solid tumours (including gastric cancer and breast cancer). Anbenitamab received its first approval in China on 27 May 2026. Anbenitamab, in combination with chemotherapy, is approved for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have previously received at least one trastuzumab-containing therapy. This article summarizes the milestones in the development of anbenitamab leading to this first approval for gastric or GEJ cancer.

Breast cancer brain metastases (BCBMs) represent a critical unmet clinical need in metastatic breast cancer (MBC) and the identification of novel therapeutic targets is urgently needed in this context. In this study, we describe clinically actionable targets in BCBMs using comprehensive genomic profiling. Genomic DNA was extracted from formalin-fixed paraffin-embedded archival BCBM samples and analyzed using the commercially available Agilent SureSelect V6 whole exome sequencing (WES) kit and an Illumina NovaSeq 6000 platform. Pathogenic alterations were classified as actionable alterations (AAs) if they met the updated MBC or tumor-agnostic ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) I or II criteria of the ESCAT scale. WES data from 56 BCBM samples were available [33.9% hormone receptor (HR)-negative/human epidermal growth factor receptor (HER)2-negative; 25.0% HR-positive/HER2-negative; and 38% HER2-positive]. ESCAT I/II AAs were detected in 76.8% (n = 43) of all BCBMs and the most frequently detected AAs were in genes involved in the homologous recombination repair pathway (BRCA1/BRCA2/PALB2; 53.6% overall). Biallelic inactivation of BRCA1, BRCA2, or PALB2 was observed in 19.6% of samples, with higher rates in HER2-negative BCBMs (26% in HR-negative /HER2-negative and 21% in HR-positive/HER2-negative). ESCAT I/II PIK3CA/AKT1/PTEN pathway alterations were present in 48.2% of samples and, in particular, in 50% of HR-positive/HER2-negative BCBMs. No ESR1 mutation was detected in HR-positive/HER2-negative BCBMs. The prognostic impact of previously described AAs was evaluated overall and according to breast cancer subtype. Twenty-three BCBMs (41%) were classified as HER2-positive; among these, 3 (13%) presented a hotspot PIK3CA mutation and 7 (30%) presented a PTEN deletion. Among patients with HER2-positive BCBMs, the identification of a hotspot PIK3CA mutation was significantly associated with worse prognosis. ESCAT I/II actionable genomic alterations are frequent in BCBMs, highlighting the potential for genomically targeted treatments in this setting.

Obesity is an established risk factor for postmenopausal hormone receptor-positive breast cancer, largely through estrogen-mediated pathways. Emerging evidence suggests that obesity-related metabolic dysfunction may also contribute to the risk and aggressive biology of receptor-negative breast cancer, particularly TNBC, among premenopausal women and populations undergoing rapid metabolic transition. This review evaluates epidemiologic, mechanistic, and translational evidence linking metabolic dysfunction to TNBC. Observational studies and pooled analyses report modest but reproducible associations between adiposity and TNBC, stronger in some metabolically high-risk populations but heterogeneous across studies. BMI-based Mendelian randomization generally yields inverse associations with overall breast cancer, whereas bariatric-surgery studies suggest lower overall incidence without establishing TNBC-specific effects. These discordant causal-inference findings do not demonstrate that obesity directly causes TNBC. Mechanistic studies indicate that adipose inflammation, adipokine imbalance, insulin/IGF-1 signaling, and immune remodeling can promote inflammatory signaling, metabolic adaptation, and epithelial plasticity. These processes support biologic plausibility but do not demonstrate de novo conversion to a receptor-negative subtype in vivo. Current evidence supports a model in which obesity-related metabolic dysfunction may create a breast microenvironment favoring tumor-promoting inflammation and aggressive features associated with TNBC. Priorities include refined metabolic phenotyping, biomarker-driven risk stratification, validation in human-relevant models, and biomarker-enriched feasibility studies testing whether modifying metabolic dysfunction alters intermediate metabolic or tissue endpoints. An evidence-graded framework is needed to distinguish association, biologic plausibility, and causal inference.

Leptomeningeal metastasis (LM), an uncommon yet highly fatal condition, involves malignant tumor infiltration of the meninges resulting in progressive neurological deterioration and severe quality-of-life impairment. LM remains largely refractory to treatment and lacks standardized treatment consensus, with a low intracranial objective response rate (iORR) of 20% and a short median intracranial progression-free survival (iPFS) of 2.2 months. In this study, adult patients with breast cancer-related LM received intraventricular thiotepa combined with methotrexate. The primary endpoint was achieved with an iORR of 45.8% (11 out of 24, 95% CI: 25.55-67.18%), and the intracranial disease control rate was 58.3% (14 out of 24, 95% CI: 36.64-77.89%). From treatment initiation, the median iPFS and overall survival were 7.9 months (95% CI: 5.3-not estimable) and 11.7 months (95% CI: 5.7-not estimable), respectively. Grade 3-4 treatment-related adverse events occurred in 62.5% (15 out of 24) of patients, most commonly thrombocytopenia (37.5%) and leukopenia (33.3%), with no Grade 5 toxicities. The exploratory study indicated that two proteins in CSF and four plasma proteins were significantly associated with iORR. Overall, the regimen was feasible and demonstrated a manageable safety profile, with a preliminary signal of clinical benefit warranting further investigation.

Electrochemical quantification of microRNAs (miRNAs) in tumor interstitial fluid (TIF) may provide complementary molecular information for tumor microenvironment assessment, but analytical accuracy is often limited by extraction-induced biomarker loss/degradation and background interference from endogenous electroactive metabolites. Herein, a hydrogel microneedle-integrated electrochemical biosensor is developed as a complementary ex vivo molecular sensing approach for wash-free and anti-interference monitoring of miRNAs via negative-potential readout. The sensing platform employs a four-way junction (FWJ) nucleic acid nanoreservoir to encapsulate the electroactive indicator doxorubicin (DOX), which is released upon target miRNA-triggered strand displacement. The characteristic oxidation potential of DOX (-0.65 V) enables detection in a negative potential window, thereby reducing co-oxidation interference by endogenous electroactive species. The porous hydrogel microneedle architecture facilitates rapid TIF sampling and directional diffusion of released DOX toward the electrode interface. The biosensor achieved a detection limit of 1.25 pM for miRNA-21 with an interassay variability of <1.9%. Preliminary analysis of clinical TIF samples from breast cancer and healthy donors further supported the feasibility of direct miRNA detection, yielding an AUC of 0.92. This work offers a novel strategy by integrating ex vivo in situ TIF sampling with negative-potential readout to achieve wash-free and anti-interference detection of biomarkers in complex physiological matrices.

Segmenting tissues and cells in pathology images enables quantitative analysis but usually requires task-specific models or repeated spatial prompts. Here we show PathSegmentor, a foundation model that uses natural language descriptions to segment structures across anatomical regions and spatial scales. We assembled PathSeg from 21 public datasets, comprising 275,200 image-mask-label triples organized into a 3-level hierarchy of anatomical region, histological structure and object type. A single PathSegmentor model achieved the highest overall performance across 16 internal datasets and generalized to external public and clinical cohorts. Its text prompts reduced the need to identify every object with points or boxes and remained robust to variations in wording. We further used its predicted structures to explain breast cancer classification models through object-level perturbation and activation maps. These results establish a unified framework for flexible pathology segmentation with potential utility for clinically interpretable image analysis.

The potential association between micro-/nanoplastics and cancer has raised increasing concerns. However, research focusing specifically on breast cancer (BC), and particularly on triple-negative breast cancer (TNBC), remains limited, leading to a critical gap in current knowledge. This study seeks to explore potential correlative effects of micro-/nanoplastic exposure on TNBC progression. We employed scanning electron microscopy, micro-Raman spectroscopy, and pyrolysis-gas chromatography-mass spectrometry to characterize micro-/nanoplastics in BC tissues. Moreover, spatial transcriptomics (ST) analysis was applied to characterize putative molecular changes associated with polyethylene terephthalate (PET) micro-/nanoplastic exposure and TNBC progression, followed by in vitro and in vivo assays to further investigate these changes. A variety of micro-/nanoplastics were detected in human BC tissues. Among them, based on the results of the ST analysis, PET might be related to the downregulation of spermine/spermidine N1-acetyltransferase 1 (SAT1) in TNBC tumor cells and the inhibition of ferroptosis. Moreover, in vitro and in vivo data showed that, following PET treatment, SAT1 expression and ferroptosis were significantly downregulated, whereas TNBC cell proliferation and xenograft growth were significantly upregulated. Additionally, in vitro experiments further suggested that PET micro-/nanoplastics could interact with BC cells via particle endocytosis or surface adsorption. This study suggests that SAT1-dependent ferroptosis may be a potential molecular pathway that links PET micro/nanoplastic exposure to TNBC progression. This finding provides novel insights into the possible toxicological association between micro-/nanoplastic exposure and TNBC progression.

A major challenge for injectable therapeutic nanorobots is to achieve efficient and spatially precise intracellular actuation under biologically compatible field conditions. Here we introduce homotypic membrane-camouflaged magnetic nanorobots that couple selective tumor-cell internalization, low-field intracellular rotation and glutathione-responsive drug release for chemo-mechanical breast cancer therapy. The nanorobots comprise disulfide-bridged mesoporous organosilica nanohelices loaded with doxorubicin, decorated with Fe3O4 nanoparticles and cloaked with MCF-7 cancer cell membranes. The membrane cloak promotes homologous recognition and enriches magnetic actuators inside MCF-7 cells, where a rotating magnetic field drives rapid intracellular rotation and localized mechanical perturbation. Intracellular glutathione concurrently cleaves the disulfide-containing organosilica framework, triggering nanorobot degradation and doxorubicin release. This spatial coupling of mechanical injury and chemotherapy induces pronounced tumor-cell death in vitro and suppresses tumor growth by 87.03% in an MCF-7 xenograft model without obvious systemic toxicity. These findings establish homotypic intracellular localization as a strategy for programmable magneto-mechanical nanotherapy.

Artificial intelligence-empowered virtual cell models represent an emerging approach for in silico drug discovery1-3, yet most existing approaches lack large-scale, time-resolved perturbation proteomics data and interpretable frameworks for predicting therapeutic responses. Here we generated more than 38 million temporal protein-abundance measurements from systematically perturbed breast cancer cell lines, and developed ProteinTalks, a virtual cell model. Central to ProteinTalks is the synergy of this large-scale dynamic proteomic resource and the model architecture, enabling a new pretraining framework that learns transferable dynamical latent representations from temporal proteome trajectories. By modelling how proteins respond conditionally to different perturbations, this approach enables the model to function as an operational tool for diverse drug discovery tasks: predicting drug efficacy and synergy, discovering new drug combinations, probing proteins associated with drug resistance, stratifying patient responses and prioritizing drug candidates for patient organoids. It also shows robust transferability, extending beyond cell lines to patient-derived organoids and clinical biopsies, generally achieving higher performance than the selected benchmark implementations under the evaluated protocols. Together, ProteinTalks shows how scalable pretraining of transferable dynamic representations enables operational, dynamics-aware, proteomics-based virtual cell models to advance in silico drug discovery.

Breast cancer (BC) remains one of the most prevalent malignancies globally, with mastectomy frequently required as part of treatment. This creates a critical clinical demand for effective breast reconstruction strategies. Conventional reconstruction methods, such as silicone implants, autologous fat grafting, and free-flap surgery, have notable drawbacks. Scaffold-guided breast reconstruction (SGBR) is a promising alternative that relies on biocompatible, biodegradable scaffolds to support and direct the regeneration of vascularized soft tissue. This review summarizes the current state of SGBR approaches, emphasizing scaffold architecture, biomaterials, and fabrication techniques. Various scaffold configurations, including fibrous, porous, hydrogel-based, mesh-like, and composite architectures, are discussed, along with natural and synthetic polymeric biomaterials. The integration of advanced additive manufacturing (AM) technologies is also explored, highlighting their role in enabling patient-specific scaffold designs. The review outlines key biological and mechanical criteria for a successful reconstruction, with particular attention to challenges such as neovascularization and tumor recurrence. Although preclinical studies have yielded promising outcomes, clinical translation remains limited, highlighting the need for continued research to optimize scaffold functionality, integration, and long-term performance.

Despite increasing awareness of molecular subtypes of breast cancer, this heterogeneous malignant disease is still one of the leading causes of cancer death in women worldwide. Although receptor status may define the precise therapeutic targets, treatment of triple-negative breast cancer (TNBC) relies mainly on chemotherapy with accompanying side-effects. Thus, there is a need for the design and testing of more effective drug delivery systems and drug combinations. In this study, biomimetic self-assembled bovine serum albumin (BSA) capsules (Cs) co-loaded with a new drug combination, namely two drugs tanespimycin (T) and dasatinib (D), and natural compound quercetin (Q), were fabricated, and their anti-breast cancer effects were assessed. (T-D-Q)-BSA Cs were more active against TNBC cells compared to other types of breast cancer. Encapsulated drugs potentiated apoptotic cell death in TNBC cells compared to the effect of the free three-drug formulation. In TNBC cells with mutated TP53, (T-D-Q)-BSA Cs also induced necroptotic cell death accompanied by RAP1-mediated stimulation of NFκB activity and IL-6-related proinflammatory response. (T-D-Q)-BSA Cs also inhibited TNBC-based tumor growth in two zebrafish xenograft in vivo models. In conclusion, the efficacy of (T-D-Q)-BSA Cs as a novel therapeutic strategy to eradicate TNBC in vitro and in vivo was demonstrated.

The Warburg effect drives cancer cells to rely preferentially on glycolysis, resulting in diminished mitochondrial oxidative phosphorylation (OXPHOS). This metabolic phenotype limits the ability of excess copper (Cu) ions to trigger cuproptosis in dysfunctional mitochondria, leading to suboptimal therapeutic outcomes. Therefore, remodeling tumor energy metabolism to counteract the Warburg effect represents a pivotal strategy to enhance cuproptosis efficacy. Herein, we developed a Cu(I)-stabilized metal-organic framework nanoplatform (CuTz-1) encapsulated by Azurin (CuTz-1@Azurin) as a cuproptosis sensitizer. Mechanistically, Azurin increases p53 protein levels by intercepting MDM2-mediated ubiquitin-proteasome degradation. Elevated p53 subsequently inhibits pyruvate kinase M2 (PKM2) activity, suppressing glycolysis, while simultaneously promoting mitochondrial OXPHOS-collectively shifting cellular metabolism from glycolysis toward mitochondrial respiration and sensitizing tumor cells to Cu-induced proteotoxic stress. In addition, CuTz-1@Azurin triggers oxidative stress via reactive oxygen species (ROS) generation and glutathione (GSH) depletion, which act together with p53-mediated apoptosis to suppress tumor growth. Meanwhile, the oxidation of Cu(I) to paramagnetic Cu(II) enables real-time monitoring of the therapeutic process by magnetic resonance imaging (MRI). Both in vitro and in vivo results demonstrate good antitumor performance of CuTz-1@Azurin. This study highlights the potential of Azurin-mediated metabolic regulation as a promising strategy to potentiate cuproptosis for combined cancer therapy.

The inactivation of tumour suppressor genes is a key step in cancer development, and is usually achieved by homozygous loss. In prostate cancer, however, large genomic regions are often hemizygously lost, which complicates the identification of putative tumour suppressors in these regions. Here, we develop Epi2Hit, an integrative computational method that leverages whole genome sequencing, epigenomic profiling and gene expression to identify biallelic inactivation of tumour suppressor genes involving DNA methylation of promoter and enhancer regions of one allele and genomic loss of the other allele. We apply Epi2Hit to a cohort of 2,021 prostate cancers to discover tumour suppressor genes. In particular, we identify epigenetic biallelic inactivation of ZFHX3 at a recurrence level similar to TP53. Biallelic inactivation of ZFHX3, a transcriptional repressor, leads to upregulation of oncogenes, including MYC and a shorter time to metastasis. Finally, we provide evidence that epigenetic silencing as 2nd hit is particularly enriched in regions with nearby essential genes, precluding homozygous loss.

The Breast Cancer Susceptibility Gene (BRCA)-associated tumors represent a constantly evolving and intriguing scenario in oncology, in which the availability of novel systemic treatment, mainly including the poly (ADP-ribose) polymerase (PARP) inhibitors, has enabled an improved survival benefit in clinical subgroups. The expanding regulatory approvals of PARP inhibitors have inevitably reshaped the clinical indications for BRCA testing, moving the BRCA1/2 profiling from the traditional and preventive workflows to therapeutic paths. Despite advances in technology and treatment, substantial limitations remain in current genetic and genomic tools for the detection of deleterious BRCA1/2 variants. Germline and tumor tissue testing provide only a snapshot of a patient's disease, failing to capture the dynamic and longitudinal aspects of tumor clonal evolution. In this scenario, liquid biopsy (LB) profiling of BRCA1/2 genes, primarily as circulating tumor DNA, represents a highly active area of research potentially affecting many aspects of cancer screening, diagnosis, and monitoring in individuals who are carriers of BRCA1/2 deleterious variants. Beyond the attractive potential to surrogate the tumor tissue testing, to overcome the cancer spatial and temporal heterogeneity, and to monitor the tumor mutational profile over time, accurately detecting all clinically relevant BRCA genetic variants and epigenetic modifications using LB remains technically challenging.

Tissue-resident macrophages (TRMs) are long-lived immune cells strategically distributed across organs, where their functional plasticity enables both homeostatic maintenance and pathological dysfunction. This review provides a comprehensive analysis of TRM biology in inflammation and cancer. We first delineate the heterogeneity and developmental origins of TRM subsets across organs, highlighting how organ-specific niche signals create distinct vulnerability patterns. We then dissect macrophage dysfunction during sepsis, tracing their trajectory from protective anti-infectious immunity through critical tipping points to immunoparalysis. Next, we examine additional inflammatory contexts, including sterile inflammation, autoimmune inflammation, Type 2 inflammation, and metabolic inflammation, each revealing distinct facets of macrophage functional plasticity. In parallel, we examine how the tumor microenvironment chronically co-opts TRMs, transforming them into tumor-associated macrophages that promote angiogenesis, suppress antitumor immunity, facilitate metastasis, and support cancer stem cells (CSCs). Then, a systematic cross-disease comparison reveals shared mechanisms that underlie the opposing functional outputs of macrophages in inflammation and cancer. Finally, we evaluate emerging therapeutic strategies and propose a paradigm shift from functional blockade toward precise recalibration of macrophage function to restore immune balance across both disease categories. Together, this review highlights the therapeutic potential of targeting shared macrophage regulatory nodes to restore immune balance across inflammation and cancer.

Limited efficacy of neoadjuvant chemotherapy (NAC) in pancreatic ductal adenocarcinoma (PDAC) underscores the need for novel combination strategies and a deeper understanding of metabolic determinants of chemoresistance. Here we identify methylmalonate semialdehyde dehydrogenase (MMSDH), a valine catabolism enzyme, as a driver of gemcitabine (GC) resistance. Hypoxia induces GCN5-mediated lactylation of MMSDH at K113. Lactylated MMSDH interacts with acyl-CoA synthetase long-chain family member 4 (ACSL4), generating propionyl-CoA to facilitate KAT8-mediated ACSL4 K606 propionylation. This modification enhances ACSL4-HSC70 binding, promoting its degradation through chaperone-mediated autophagy. Critically, this MMSDH-mediated ACSL4 propionylation correlates with low ACSL4 levels and poor NAC response in recipients. Combining dietary valine restriction with GC synergistically induces ferroptosis and suppresses tumor growth. Blocking MMSDH-K113la disrupts this axis, potentiating GC-induced ferroptosis and inhibiting tumor progression. These findings reveal a previously unknown mechanism of ferroptosis evasion through valine metabolism and ACSL4 regulation, nominating the GCN5-MMSDH-ACSL4 axis as a therapeutic target to enhance PDAC chemosensitivity.

Hepatocellular carcinoma (HCC) exhibits poor patient outcomes due to its propensity for metastasis, yet the mechanisms linking metabolic dysregulation and immune evasion remain unclear. This study reveals that reduced hyodeoxycholic acid (HDCA) levels, coupled with elevated tumor-derived extracellular vesicles (EVs) carrying the long non-coding RNA MSTRG171708, correlate with aggressive HCC progression and enhanced lung metastasis. Mechanistically, MSTRG171708-enriched EVs are internalized by regulatory T (Treg) cells, stabilizing the HIF-1α/PKM2/PHD3 axis and triggering a metabolic shift toward glycolysis, thereby augmenting Treg migratory capacity and fostering an immunosuppressive microenvironment conducive to metastasis. Furthermore, HDCA suppresses EVs release by transcriptionally downregulating RAB27 and SNAP23, key mediators of exosome biogenesis, and effectively curtails metastatic burden in vivo. Clinically, high MSTRG171708 levels in HCC patients are associated with decreased HDCA levels and increased Treg infiltration. These findings establish HDCA-mediated regulation of EVs trafficking as a critical link between epigenetic modulation and immunometabolic reprogramming, proposing HDCA restoration as a novel therapeutic strategy to impede HCC metastasis.

Epigenetic dysregulation is a hallmark of cancer and contributes to tumor initiation, progression, metastasis, and therapeutic resistance. Consequently, epigenetic drugs (epidrugs) targeting DNA methylation, histone modifications, and chromatin-associated proteins have emerged as an important class of anticancer agents. Approved therapies such as DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis) have demonstrated clinical benefit, particularly in hematological malignancies; however, their efficacy is often limited by off-target toxicity, acquired resistance, and incomplete target selectivity. In recent years, metallorganic compounds have gained attention as a novel generation of epigenetic modulators. The incorporation of metal centers provides unique structural, redox, and coordination properties that enable interactions with multiple epigenetic targets and facilitate the design of multifunctional agents. This review summarizes the major classes of epidrugs and discusses emerging metallorganic epigenetic therapeutics based on ruthenium, platinum, tin, copper, iridium, iron, technetium, rhenium, and gold. We examine their mechanisms of action against key epigenetic regulators, including DNMTs, HDACs, histone methyltransferases, bromodomain proteins, and chromatin-associated complexes. Particular attention is given to the potential of metal-based epidrugs to overcome therapeutic resistance through multimodal mechanisms that combine epigenetic reprogramming with modulation of DNA damage responses, oxidative stress, protein homeostasis, and chromatin organization. Although most metallorganic epidrugs remain in preclinical development, accumulating evidence suggests that they may offer advantages over conventional organic epigenetic inhibitors by enabling multi-target engagement and more durable antitumor responses. Together, these findings highlight the growing potential of metal-based epigenetic therapies and support their further development as innovative strategies for precision oncology.

The von Hippel-Lindau (VHL) gene encodes the core substrate-recognition subunit of the Cullin2-RING E3 ubiquitin ligase complex, regulating cellular oxygen sensing and proteostasis. While targeting the canonical VHL-hypoxia-inducible factor (HIF) axis (e.g. belzutifan) has improved advanced clear cell renal cell carcinoma (ccRCC) management, intrinsic non-responsiveness and acquired resistance to HIF-2α inhibitors present major clinical limitations. Expanding beyond the HIF-centric paradigm reveals a broader network of non-canonical VHL targets, offering new opportunities for therapeutic development across ccRCC and pan-cancer contexts. This review provides an evidence-graded synthesis of novel VHL targets spanning epigenetic regulation (e.g. ZHX2, SETDB1, METTL3/METTL14), metabolic reprogramming (e.g. NDRG3, TFAM), extracellular matrix architecture (e.g. fibronectin, COL4A2), and immune modulation (e.g. TBK1). Supporting evidence across these targets ranges from direct biochemical ubiquitination to indirect downstream observations, derived predominantly from preclinical cell-line and xenograft models. Disruption of VHL and these non-HIF networks contributes to oncogenesis across diverse malignancies. Translating these mechanistic insights catalyzes two distinct therapeutic modalities. For VHL-deficient malignancies, selectively intercepting unshielded downstream effectors with small-molecule inhibitors provides rational, vulnerability-targeted salvage strategies. Conversely, in VHL-proficient malignancies, the exceptional chemical tractability of VHL has been repurposed by proteolysis targeting chimeras (PROTACs). VHL-recruiting PROTACs hijack operational ligase machinery to degrade targeted oncogenic drivers, including some previously "undruggable" oncogenes. These next-generation degraders offer potential biomarker-driven strategies to overcome current therapeutic bottlenecks in ccRCC and other associated malignancies. However, current evidence derives predominantly from in vitro and animal models. Realizing the clinical potential of VHL-targeted strategies requires addressing key unresolved questions regarding substrate directness, tissue tropism, and resistance trade-offs. Further investigating these core mechanistic and pharmacological bottlenecks will be essential to guide next-generation therapies in VHL-associated malignancies.

The dismal prognosis of breast cancer brain metastasis (BCBM) is attributed to a maladapted tumor microenvironment. This study was aimed at deciphering the role of novel intercellular communicators, tumor-derived migrasomes, in driving BCBM progression, with a focus on their ability to co-opt brain-resident microglia. Migrasomes were isolated and characterized from brain-tropic (231-BR; Mig-BCBM) and parental breast cancer cells, patient-derived metastatic breast cancer tissues, and mice BCBM tissues. The functional axis was delineated through an integrative approach encompassing proteomics, in vitro co-culture systems, in vivo brain colonization assays, genetic perturbations, and a pharmacological intervention with the clinical-stage TGFβR1 inhibitor galunisertib. Mig-BCBM were internalized by microglia, thus triggering their repolarization to a pro-tumorigenic, M2-like state, both in vitro and in vivo. Proteomic profiling identified integrin β3 (ITGβ3) as a key regulator selectively packaged into Mig-BCBM. Mechanistically, migrasomal ITGβ3 activated the PI3K/AKT pathway in microglia, thus driving M2 polarization. These reprogrammed microglia secreted high levels of TGFβ1, which in turn fostered a metastatic niche by inducing Smad2/3-dependent epithelial-mesenchymal transition (EMT) in tumor cells. Crucially, we uncovered a self-amplifying feedforward loop in which microglial-derived TGFβ1 transcriptionally upregulates TSPAN4 via EGR1 in cancer cells, thus enhancing migrasome biogenesis and subsequent ITGβ3 loading. Disrupting this loop with galunisertib potently inhibited BCBM outgrowth and colonization in vivo, without systemic toxicity. This study identified a targetable circuit in BCBM wherein tumor-derived migrasomes, via ITGβ3, engage microglia in a TGFβ1-centered crosstalk. Because this self-reinforcing ITGβ3-TGFβ1 axis sustains the pro-metastatic niche, its disruption might provide a rational therapeutic strategy.

Gastric cancer (GC) displays marked heterogeneity under the Lauren classification, yet the metabolic determinants of subtype divergence remain unclear. Here, we identify Malonyl-CoA:ACP transacylase (MCAT), a Lauren subtype-associated gene encoding a key mitochondrial fatty acid synthesis (mtFAS) enzyme, as a subtype-specific tumor suppressor in GC. Integrative multi-omics profiling revealed that MCAT expression is enriched in intestinal-type GC and correlates with favorable prognosis. Mechanistically, MCAT overexpression drives metabolic reprogramming through mitochondrial free fatty acid overload, suppressing β-oxidation while elevating mitochondrial reactive oxygen species (ROS), which triggers P53 phosphorylation at Ser15. This event concurrently activates PINK1/Parkin-mediated mitophagy and suppresses the SLC7A11/GPX4 axis to induce ferroptosis. Genetic rescue experiments confirmed that P53-Ser15 phosphorylation is essential for both mitophagy and ferroptosis induction. Endogenous MCAT levels are sufficient to determine basal ROS/P53/mitophagy/ferroptosis axis activity, and knockdown in high-expressing cells reverses these phenotypes, supporting a physiological, threshold-dependent role. In vivo, MCAT overexpression suppresses tumor growth and enhances mitophagy and ferroptosis markers. Collectively, these findings establish MCAT as a metabolic switch that links mtFAS to ROS/P53-dependent cell death, providing a potential biomarker and therapeutic target for GC.

Cell death is essential for maintaining internal stability and metabolic balance in the human body and plays a key role in regulating physiological and pathological processes. Advances in understanding the link between pathological mechanisms and cell death have provided new insights into diagnosis and treatment. A novel, pivotal form of regulated cell death, termed disulfidptosis, has recently been identified. This is characterized by glucose deprivation, elevated expression of solute carrier family 7 member 11 (SLC7A11), accumulation of disulfides such as cystine, disulfide stress, and cell death. These distinctive characteristics indicate that disulfidptosis is mechanistically distinct from other known forms of cell death. Its unique induction mechanism implies its therapeutic potential and warrants further investigation. This cell death process is primarily triggered by intracellular NADPH exhaustion and subsequent actin cytoskeleton collapse, and it exhibits complex crosstalk with ferroptosis, cuproptosis, pyroptosis, necroptosis, apoptosis and autophagy. The core execution relies on the Rac-WRC-Arp2/3 pathway, with emerging involvement of ER stress and p38 MAPK signaling. In this review, we discuss the molecular mechanisms and current status and prospects of targeted therapy for disulfidptosis, as well as its role in cancer and other diseases, including but not limited to neurodegenerative, cardiovascular, autoimmune, and infectious conditions. We hope to provide a comprehensive and systematic framework, including mechanistic analysis, application strategies, clinical translation, and future research directions, to guide in-depth investigation.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, and its pathogenesis and treatment strategies remain major challenges. Recent advances in single-cell RNA sequencing and lineage tracing have revealed that vascular smooth muscle cells (VSMCs) are not merely passive structural components of atherosclerotic plaques, but highly plastic participants that undergo clonal expansion, phenotypic modulation, and transdifferentiation into functionally diverse cell states. These findings have prompted the emergence of an "athero-oncology" framework, which explores selected tumor-like cellular programs in VSMCs during AS without equating atherosclerosis with cancer. In this review, we summarize the evidence supporting VSMC-derived clonal expansion and phenotypic diversification in atherosclerotic lesions and discuss key mechanisms involved in this process, including proliferative expansion and survival programs, metabolic reprogramming, epigenetic regulation, DNA damage and genomic stress, VSMC senescence, pathological angiogenesis, and remodeling of the inflammatory and immune microenvironment. We further highlight shared signaling pathways between VSMC-driven plaque remodeling and tumor biology, while emphasizing fundamental differences between AS and malignant disease in growth limitation, mutational burden, metastatic potential, and clinical behavior. Finally, we discuss oncology-inspired therapeutic opportunities and boundaries, including pathway-level targeting of proliferative, metabolic, epigenetic, and inflammatory programs, as well as the risks of directly repurposing anticancer therapies for chronic vascular disease. This framework may provide new insights into vascular biology and therapeutic development.

Cancer-associated fibroblasts (CAFs) are key stromal components of the tumour microenvironment (TME) that profoundly influence tumour progression. However, CAFs exhibit pronounced phenotypic and functional heterogeneity, and whether conserved CAF subtypes with shared functional hallmarks exist across different cancer types remains unclear. We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME. We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways. We identified a conserved syndecan 1 (SDC1) + CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1+ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis. Our study establishes SDC1+ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

Immune checkpoint inhibitors have transformed non-small cell lung cancer (NSCLC) treatment. Understanding the tumor-immune interactions that dictate sensitivity to PD-1 blockade is essential for improving outcomes and optimizing immunotherapy personalization. We performed compartment-specific (tumor/immune) spatial proteomic profiling (GeoMx) on a discovery cohort of 104 patients with advanced, PD-L1-high (tumor proportion score ≥50%) NSCLC treated with first-line pembrolizumab. Identified markers were further assessed using orthogonal methods in two independent early-stage NSCLC cohorts treated with neoadjuvant/perioperative chemo-immunotherapy: (a) NADIM trial (n=36) with bulk RNA-seq and (b) NeoITX_H12O cohort (N=41) with quantitative immunohistochemistry. Potential baseline prognostic value without immunotherapy was evaluated in the TCGA dataset (N=940). Functional validation was assessed using in vitro and in vivo (nude and syngeneic) models. We identified tumor-cell OX40L, but not immune-cell OX40L, as the single marker significantly associated with prolonged progression-free survival (PFS) and overall survival under single-agent pembrolizumab in patients with PD-L1-high tumors. Spatially resolved analysis linked tumor-intrinsic OX40L to an active immune microenvironment with increased antigen presentation. In both neoadjuvant/perioperative cohorts, high OX40L levels in residual tumors from patients with non-pathological complete response were associated with superior PFS. Conversely, no significant association with survival was observed in the immunotherapy-naïve TCGA cohort. Functional studies confirmed that OX40L-expressing NSCLC cells directly co-stimulate T cells in vitro and significantly enhance anti-PD-1 efficacy in vivo (p=0.0005), without affecting intrinsic tumor growth. OX40L expressed by tumor cells contributes to an enhanced efficacy of PD-1 blockade in patients with NSCLC. These findings may open new therapeutic avenues and potentially contribute to improving immunotherapy personalization in this disease.

Our Future Health is a prospective study aiming to recruit 5 million UK-resident adults to enable discovery and translation of disease prevention, detection and treatment approaches. So far, more than 2.5 million have enrolled, and baseline phenotypic data are available for >1.9 million participants. Here we provide an assessment of phenotypes-self-reported health-related behaviors, geolocation, diagnoses and medication, in- and outpatient visits, cancer registry and cause of death-and comparison of disease patterns against national estimates and the UK Biobank cohort. Sociodemographic, lifestyle and health-related characteristics reflected UK population patterns; all but one minority ethnic group and the most socioeconomically deprived groups were underrepresented. The prevalence of several major self-reported conditions, particularly mental health conditions such as depression and anxiety, was higher than national estimates and directionally concordant with the UK Biobank (r = 0.78). Associations with known clinical correlates replicated across both cohorts (r = 0.80). Medication-use patterns and cancer prevalence followed expected age-related gradients, with lower lung cancer rates than national data. As recruitment progresses, electronic health records can help specify disease patterns and systematically assess biases.

Uncommon EGFR mutations (ucEGFR mut) account for 10%-15% of epidermal growth factor receptor (EGFR) oncogenic alterations in non-small cell lung cancer (NSCLC) and display heterogeneous sensitivity to EGFR tyrosine kinase inhibitors. Clinical, pathological, and molecular data from patients with advanced NSCLC harboring ucEGFR mut (excluding ex20 insertions) and treated with first-line osimertinib were retrospectively collected from the Italian ATLAS registry. From January 2019 to January 2025, 212 patients were included. Median age was 69 years (range 24-90); 61.3% were female and 47.6% had a smoking history. Exon 19 deletions/insertions (ex19 delins) were the most frequent ucEGFR mut (55.7%), followed by L816Q (10.8%), G719X (8.5%), and D761N (7.5%). Tumor protein p53 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) comutations were present in 43.3% and 10.4% of cases. The overall response rate (ORR) was 66% [95% confidence interval (CI) 58-73], median progression-free survival (mPFS) was 18.3 months (95% CI 14.6-19.7), and median overall survival (mOS) was 34.5 months (95% CI 26.1-42.9). Patients with ex19 delins showed superior outcomes versus other ucEGFR mut: ORR (74.3% versus 55%, P = 0.007), mPFS (25.3 versus 12.6 months, P = 0.001), and mOS (41.7 versus 30.4 months, P = 0.03), as well as different resistance mechanisms. Targetable acquired alterations (mesenchymal-epithelial transition amplification and C797S mutations) were detected predominantly in patients with ex19 delins, leading to the use of second-line molecularly matched therapies mainly in this subgroup. Patients with ex19 delins showed similar survival outcomes (25.3 versus 25.4 months, P = 0.55) and resistance patterns compared with a cohort of patients harboring the common exon 19 deletion (ELREA) extracted from the ATLAS registry. Among ex19 delins, variants starting at codon 746 achieved longer survival compared with those starting at codon 747. Osimertinib exhibited meaningful differences in efficacy and resistance mechanisms across distinct ucEGFR mut. Notably, ex19 delins showed comparable survival outcomes and resistance patterns to classical ex19 deletions, albeit with heterogeneous osimertinib sensitivity depending on the deletion-insertion starting codon.

Neoadjuvant chemoimmunotherapy is standard for resectable non-small-cell lung cancer (NSCLC) but response assessment is challenging due to pseudoprogression, which may lead to unnecessary cancellation of surgery. We characterized pseudoprogression and developed a clinical strategy to distinguish it from true progression after neoadjuvant immune checkpoint inhibitor (ICI) therapy. We retrospectively analyzed data from 283 patients with resectable NSCLC receiving neoadjuvant ICI (n = 235) or tyrosine kinase inhibitor (n = 48) therapy from January 2021 to December 2023. Positron emission tomography-computed tomography (PET-CT) scans were acquired at baseline and preoperatively. Responses were evaluated using RECIST 1.1 and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Predictors of pseudoprogression were evaluated using multivariable logistic regression. Model performance was assessed in an independent validation cohort (n = 95). By RECIST 1.1, 26 of 283 patients (9.2%) had progressive disease (PD), all in the ICI cohort. By EORTC criteria, the number with PD increased to 71 of 283 (25.1%). Despite PD, all 26 patients underwent R0 resection; complete pathological response (CPR) and major pathological response (MPR) rates were 53.8% and 65.3% compared with 30.0% and 49.0%, respectively, in patients without PD. Among 71 with progressive metabolic disease, 69 (97.2%) achieved R0; CPR and MPR were 38.0% and 54.9%, respectively. Primary-tumor progression had lower MPR than nodal or distant progression (23.1%, 58.2%, and 73.3%, respectively, P = 0.020). Pseudoprogression occurred in 7.2% based on CT, increasing to 16.2% with PET-CT. A ≥53.1% reduction in primary-tumor maximum standardized update value (SUVmax) identified pseudoprogression [area under the curve (AUC) 0.865, sensitivity 94.7%, specificity 74.1%]. A multivariable model combining change in SUVmax, longest diameter change, smoking status, and histology showed excellent discrimination (AUC 0.935) and remained robust in validation (AUC 0.859). Imaging-defined progression after neoadjuvant ICI may reflect pseudoprogression, most commonly nodal or distant lesions without primary tumor progression. A validated model incorporating primary-tumor metabolic response and clinical features improves discrimination of pseudoprogression and may support decision making to avoid inappropriate cancellation of potentially curative resection.

Lung cancer with multiorgan metastasis remains the leading cause of cancer death. Current CT imaging and biopsy are suboptimal for detecting early tumors or subclinical metastases. We address this gap using LUAD with LKB1/STK11 inactivation, which alters collagen via focal adhesion kinase activation. Collagen I overexpression in the tumor microenvironment and invasive edge was identified as a biomarker. We developed hProCA32.Collagen, a protein MRI contrast agent targeting collagen I, which exhibits 10-fold higher relaxivity than clinical GBCAs, with strong Gd3+ binding, high stability, and low toxicity risk. Precision MRI with hProCA32.Collagen enables early, noninvasive detection and quantification of lung tumors and metastases with improved contrast, outperforming CT and standard MRI. This is a demonstration of simultaneous MRI detection of primary tumors and metastases in the lung and adrenal glands, with collagen mapping. This approach offers a radiation-free tool for early diagnosis, staging, and monitoring in LUAD.

Lactylation is an emerging post-translational modification that is well established for its involvement in epigenetic regulation. However, its functional significance and regulatory mechanisms in non-small cell lung cancer (NSCLC) remain poorly understood. In this study, integrated proteomic and lactylomic analyses of clinical NSCLC specimens and matched adjacent normal tissues showed that USP7 (ubiquitin specific peptidase 7) was upregulated and USP7 K1084 lactylation was increased in NSCLC. Knockout of USP7 or inhibition of USP7 lactylation impaired cellular mitophagy, resulting in mitochondrial damage and attenuated NSCLC tumorigenicity. We identified CREBBP/CBP (CREB binding lysine acetyltransferase) as the key lactyltransferase responsible for USP7 K1084 lactylation. USP7 lactylation induced its localization to mitochondria and increased its interaction with PINK1 (PTEN induced kinase 1), promoting PINK1 deubiquitination and stabilization. Pharmacological inhibition of CREBBP reduced USP7 lactylation levels and promoted PINK1 ubiquitination and degradation, exerting antitumor effects in vitro and in vivo. Analysis of NSCLC clinical specimens showed that the protein levels of USP7, CREBBP, and PINK1 were positively correlated, and their high expression was associated with poor patient prognosis. Collectively, our findings establish the CREBBP-USP7-PINK1 axis as a promising therapeutic target for NSCLC treatment.Abbreviations: CHX: cycloheximide; CREBBP/CBP: CREB binding lysine acetyltransferase; DUB: deubiquitinating enzyme; IHC: immunohistochemistry; IP: immunoprecipitation; KO: knockout; LDHA: lactate dehydrogenase A; MS: mass spectrometry; NALA: L-sodium lactate; NSCLC: non-small cell lung cancer; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; ROS: reactive oxygen species; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TUBE: tandem ubiquitin binding entity; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; WT: wild type.

Tyrosine kinase inhibitors (TKIs) targeting anaplastic lymphoma kinase (ALK) have transformed the treatment landscape of ALK fusion-positive non-small-cell lung carcinoma (ALK-positive NSCLC), but the limited options for patients who progress on approved TKIs highlight a continued need for an orthogonal therapeutic approach1,2. TRI-611 is a potent, brain-penetrant molecular glue degrader of ALK fusion proteins with the potential to address this need. TRI-611 promotes the proximity of the ALK kinase domain and CRL4 substrate adaptor CRBN through a unique degron interface distal from the kinase active site. The unique binding interface of TRI-611 leads to selectivity across the proteome including known CRBN neosubstrates and other kinases. TRI-611 treatment induces degradation of all forms of ALK fusion proteins, including wild-type and ALK TKI-resistant versions, leading to regression of cell line and patient-derived subcutaneous and intracranial tumour models of ALK-positive NSCLC. TRI-611 can be combined with orthosteric ALK TKIs, achieving synergistic and durable tumour regressions. TRI-611 represents to our knowledge the first clinical-stage molecular glue degrader targeting an oncogenic gene fusion and has the potential to expand the arsenal of therapeutic options for patients with ALK-positive NSCLC .

KRAS is the most frequently mutated oncogene in human cancers, and its G12C variant is highly prevalent in lung adenocarcinoma (LUAD) and predicts poor clinical outcomes. However, the metabolic mechanisms underlying KRAS-driven malignancy and therapeutic resistance remain incompletely understood. Here, we identify alanyl-tRNA synthetase 1 (AARS1) as a previously unrecognized metabolic effector of KRAS signaling. AARS1 protein-but not its mRNA-is markedly upregulated in LUAD tissues, owing to impaired selective autophagic degradation mediated by the E3 ligase TRIM21. Mechanistically, KRAS G12C activates ERK2-dependent phosphorylation of AARS1 at Ser882, disrupting its interaction with TRIM21 and preventing autophagic turnover. Stabilized AARS1 drives metabolic reprogramming by catalyzing lysine lactylation of PDHA1 (K336) and ENO1 (K71), thereby suppressing OXPHOS, enhancing glycolysis, and promoting tumor progression. Importantly, KRAS G12C-induced AARS1 phosphorylation confers resistance to Sorafenib. Blocking AARS1 phosphorylation using the natural compound Hypericin restores autophagic degradation of AARS1, reverses metabolic reprogramming, and markedly sensitizes KRAS-mutant LUAD organoids and PDX models to Sorafenib. These findings uncover AARS1 as a lactate-sensing oncogenic effector downstream of KRAS G12C and highlight the therapeutic potential of targeting AARS1 phosphorylation to overcome drug resistance in LUAD.

Non-small cell lung cancer (NSCLC) is one of the frequently occurring cancers characterized by molecular heterogeneity and multiple immune cell infiltration patterns, which are associated with treatment sensitivity and resistance. However, the specific microenvironmental cells and their mechanisms that lead to treatment resistance in patients need to be explored in greater depth. On the basis of patients receiving neoadjuvant therapy in our center, a multicenter, multicohort NSCLC spatial transcriptome, single-cell transcriptome, T-cell receptor repertoire sequencing, bulk RNA transcriptome, phosphorylated proteome, genome mutation, and clinical data were included for a comprehensive assessment of the therapeutic and prognostic impact of HIF1A+ CSF3R+ neutrophils in NSCLC. In vitro experiments validated the functional phenotype of HIF1A+ CSF3R+ neutrophils and co-localization interactions with other cellular subpopulations. Gradient boosting machine (GBM) constructed region of interest (ROI) models for evaluation. Computer-aided drug design (CADD) was used to predict targeted small molecule drugs, and in vivo mouse models were constructed to assess the effectiveness of the combination treatment regimen. Centered on HIF1A+ CSF3R+ neutrophils, recruited exhausted T cells and stromal cells form a hypoxic niche within the tumor region, which was enriched in non-response patients. ROI composed of these specific cellular subpopulations, associated with senescence and glycolysis, accurately predicting NSCLC progression, prognosis, and microenvironment composition. CADD analysis identified that platycodin-D2 specifically targeted CSF3R, reducing HIF1A expression and inhibiting neutrophil activity. Combining navitoclax, platycodin-D2 with anti-programmed cell death protein 1 (PD-1) significantly suppressed tumor proliferation and improved the immunosuppressive microenvironment. Our study emphasized the role of HIF1A+ CSF3R+ neutrophils in immunotherapeutic resistance of NSCLC, constructed a microenvironmental immune dysregulation network in a hypoxic ecological niche with HIF1A+ CSF3R+ neutrophils as the center. Platycodin-D2 specifically targeted HIF1A+ CSF3R+ neutrophils, enhancing the efficacy of anti-PD-1 therapy in NSCLC.

Across various cancer entities, a wide array of subtypes of B cells that infiltrate tumors can be identified. These subtypes confer these cells with high adaptability in their functions and significant involvement in tumor progression. Tumor-infiltrating B cells act as distinctive microenvironmental mediators that build tertiary lymphoid structures, secrete diverse factors, and generate a wide antibody repertoire, thereby offering a valuable indicator of immunotherapy response. Recent clinical trials have demonstrated that intervening in tumor-infiltrating B cells can be an effective treatment strategy for tumors, including common types such as breast cancer, colorectal carcinoma, and non-small cell lung cancer. These findings suggest that tumor-infiltrating B cells should not be overlooked as therapeutic targets, as they offer significant potential to reduce the incidence of nonresponse, drug resistance, and immune-related adverse effects commonly seen in current treatment techniques. In this review, we explore the historical development of B cells in the context of tumors. We then discuss the various subtypes of tumor-infiltrating B cells, analyzing their diverse roles in tumor development. Additionally, we delve into the signaling pathways of tumor-infiltrating B cells, intercellular crosstalk, and multilevel regulatory mechanisms. Finally, based on immune checkpoints and therapeutic targets on the surface of tumor-infiltrating B cells, we summarize the current understanding which can lead to the development of new intervention methods targeting tumor-infiltrating B cells in the future. This review aims to provide a comprehensive summary of B-cell classification and therapeutic potential, emphasizing their critical role in guiding clinical treatment strategies.

Adjuvant pembrolizumab improves disease-free survival (DFS) and overall survival (OS) versus placebo in high-risk clear cell renal cell carcinoma after nephrectomy. Recently, pembrolizumab plus belzutifan showed superior DFS over pembrolizumab alone. We assessed the efficacy of adjuvant pembrolizumab plus belzutifan versus placebo using reconstructed data from two pivotal phase III trials. Individual time-to-event data were reconstructed from digitised KEYNOTE-564 and LITESPARK-022 Kaplan-Meier curves using a validated algorithm based on numbers at risk. Datasets were pooled to enable indirect comparisons across strategies. The primary endpoint was DFS and OS was secondary. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. The pooled dataset included 2835 patients. Baseline characteristics were balanced, except for race and programmed death-ligand 1 (PD-L1), although PD-L1 assessment was limited by incomplete reporting. Pembrolizumab plus belzutifan significantly improved DFS versus placebo (HR 0.55, 95% CI 0.45-0.69, P < 0.001). Despite immature OS data, the combination showed an OS benefit over placebo (HR 0.56, 95% CI 0.35-0.89, P = 0.014). Adjuvant pembrolizumab plus belzutifan showed a substantial DFS benefit compared with placebo. In a context where factors beyond efficacy demand robust evidence of clinical benefit, these findings reinforce the value of combined immune and hypoxia-inducible factor 2α inhibition.

In the global phase III TROPION-Breast01 study, datopotamab deruxtecan (Dato-DXd) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review (BICR) versus investigator's choice of chemotherapy (ICC) in patients with previously treated, inoperable/metastatic hormone receptor(HR)-positive human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. At the final analysis, overall survival (OS) was not statistically significant. We report final results from the prespecified analysis of patients enrolled in mainland China. Patients with inoperable/metastatic HR+/HER2- breast cancer, who had disease progression on endocrine therapy and for whom endocrine therapy was unsuitable and who had received 1-2 prior lines of chemotherapy in the inoperable/metastatic setting, were randomly assigned 1 : 1 to Dato-DXd (6 mg/kg every 3 weeks) or ICC (eribulin/capecitabine/vinorelbine/gemcitabine). Dual primary endpoints were PFS by BICR and OS. Overall, 83 patients were enrolled in mainland China (Dato-DXd, n = 44; ICC, n = 39). PFS by BICR numerically favored Dato-DXd versus ICC [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.30-0.96, nominal P = 0.0329; median PFS: 8.1 versus 4.2 months]. OS numerically favored Dato-DXd versus ICC [HR 0.83 (95% CI 0.49-1.43), nominal P = 0.5028]. The rate of grade ≥3 treatment-related adverse events (TRAEs) was lower with Dato-DXd versus ICC (29.5% versus 58.3%). The most common TRAEs (any grade/grade 3-4) were nausea (47.7%/4.5%) and increased aspartate aminotransferase (40.9%/2.3%) with Dato-DXd, and neutropenia (grouped term, 58.3%/36.1%) and anemia (52.8%/8.3%) with ICC. With Dato-DXd, treatment-related AEs of special interest (grouped terms) oral mucositis/stomatitis and ocular surface events occurred in 43.2% and 47.7% of patients, respectively. In this China cohort, Dato-DXd demonstrated numerically improved efficacy versus ICC and a manageable safety profile, consistent with the global population, supporting Dato-DXd as a new treatment option for Chinese patients with previously treated metastatic HR+/HER2- breast cancer.

In the KEYNOTE-826 study, pembrolizumab (vs placebo) plus platinum-based chemotherapy (with or without bevacizumab) significantly improved progression-free survival and overall survival in participants with previously untreated persistent, recurrent, or metastatic cervical cancer at interim analysis 1 (median follow-up, 22.0 months), with continued benefit at final analysis (median follow-up, 39.1 months). Long-term follow-up is important to further inform the benefit-risk profile of anticancer treatments. To investigate 5-year efficacy and safety results of pembrolizumab plus chemotherapy (with or without bevacizumab) in previously untreated persistent, recurrent, or metastatic cervical cancer. This ad hoc exploratory analysis of the phase 3, double-blind KEYNOTE-826 randomized clinical trial was conducted in participants with previously untreated persistent, recurrent, or metastatic cervical cancer across 151 sites in 19 countries. Participants were randomly assigned to treatment between November 20, 2018, and January 31, 2020. The median follow-up for this analysis was 59.1 (range, 52.1-66.5) months (approximately 20 months after final analysis). Data were analyzed between November 20, 2018, and June 4, 2024. Pembrolizumab, 200 mg, every 3 weeks for up to 35 cycles vs placebo, each combined with platinum-based chemotherapy (with or without bevacizumab). Progression-free survival and overall survival. A total of 617 female patients were randomized. At baseline, the median age of participants was 51.0 (range, 22-82) years, with 303 participants (49.1%) having stage I/II and 190 (30.8%) having IVB disease and 446 (72.3%) having squamous cell/squamous cell carcinoma. At 5 years, the overall survival benefit was sustained with pembrolizumab plus chemotherapy in the programmed cell death ligand 1 combined positive score of at least 1 (median [IQR], 28.6 [12.3 to not reached] vs 16.5 [9.0-40.5] months; hazard ratio [HR], 0.62 [95% CI, 0.50-0.76]) and intention-to-treat (median [IQR], 26.4 [12.0 to not reached] vs 16.8 [9.1-40.1] months; HR, 0.64 [95% CI, 0.53-0.78]) populations. The progression-free survival advantage was similarly maintained (median [IQR], 10.5 [6.2 to not reached] vs 8.2 [4.2-17.1] months; HR, 0.58 [95% CI, 0.48-0.71] and median [IQR], 10.4 [6.2 to not reached] vs 8.2 [4.3-15.5] months; HR, 0.61 [95% CI, 0.51-0.74], respectively). No new safety signals were observed. No additional deaths due to treatment-related adverse events had occurred since the final analysis. In this exploratory analysis of the KEYNOTE-826 randomized clinical trial, the 5-year data confirm the durability of benefit and reinforce pembrolizumab plus chemotherapy (with or without bevacizumab) as a first-line standard-of-care option for recurrent and metastatic cervical cancer. ClinicalTrials.gov Identifier: NCT03635567.

Relapse risk and benefit of adjuvant chemotherapy after resection of appendiceal adenocarcinoma (AA) are uncertain. To identify clinicopathologic and genomic factors associated with relapse and assess efficacy of adjuvant chemotherapy in localized AA. This retrospective cohort study (January 2000 through February 2024; median follow-up, 62.6 months) used Kaplan-Meier and Cox proportional hazards modeling. It took place at the University of Texas MD (UT MD) Anderson Cancer Center with validation from Memorial Sloan Kettering Cancer Center (MSKCC). Participants included a complete localized cohort of 439 patients with stage I to III AA from UT MD Anderson, of whom 202 underwent surgery at UT MD Anderson and also included a validation cohort of 128 patients with stage II AA from MSKCC. Surgical resection with or without adjuvant chemotherapy. Rate of recurrence, recurrence-free survival (RFS), and overall survival (OS). There were 439 patients with localized AA (median age, 56.5 [IQR, 22.2-83.7] years; 50% female and 50% male) managed at MD Anderson between January 2000 and February 2024. Of 202 MDA surgical patients, 19 (9.4%) had a relapse including 9 (6%) patients with stage II and 8 (19.5%) of patients stage III disease. Five-year OS was 95.7% without vs 77.2% with relapse (hazard ratio [HR], 5.50; 95% CI, 3.07-9.83; P < .001). Relative to goblet cell tumors, mucinous (HR, 5.60; 95% CI, 2.1-15; P < .001) and enteric-type (HR, 6.60; 95% CI, 2.9-15; P < .001) histologies were independently associated with relapse, as was pathologic T4 (HR, 3.30; 95% CI, 1.9-5.7; P < .001). Importantly, poor differentiation, perforation, lymphovascular invasion, and perineural invasion, known risk factors in colorectal cancer, were not significantly associated with relapse. For the complete localized cohort, adjuvant chemotherapy was not associated with improved RFS (univariate HR, 2.06; 95% CI, 1.36-3.13; P = .001 and multivariable HR, 0.98; 95% CI, 0.43-2.28; P = .90) or OS (univariate HR, 1.80; 95% CI, 1.0-3.2; P = .04 and multivariable HR, 0.71; 95% CI, 0.24-2.1; P = .53). TP53 mutation in goblet cell tumors (HR, 6.93; 95% CI, 1.50-31.00; P = .01) and GNAS mutation in nongoblet tumors (HR, 17.0; 95% CI, 3.09-93.3; P = .001) were associated with greater risk of relapse. These results demonstrate that relapse after resection of localized AA is uncommon. Molecular profiling and histopathologic subtype refine risk. Adjuvant chemotherapy were not associated with benefit.

Emerging epidemiological and mechanistic studies suggest that Helicobacter pylori (H. pylori) exposure may be associated with colorectal cancer (CRC); however, the findings remain controversial. We aim to quantify the CRC burden potentially related to H. pylori exposure, with the overarching objective to inform prioritisation and future evaluation of H. pylori control as a candidate adjunct to existing CRC prevention efforts in settings with high prevalence and limited resources. We estimated global and regional H. pylori exposure and its epidemiological association with CRC using data from systematic reviews and meta-analyses, stratified by region, diagnostic method and eradication status, among others. We derived CRC estimates from the Global Cancer Observatory (GLOBOCAN). To evaluate the related CRC burden, we calculated the estimated related proportion (ERP) with 95% uncertainty intervals (UIs) and absolute and rate-based burdens using Monte Carlo simulations. We further examined correlations between country-level ERPs, H. pylori prevalence and CRC incidence. Lasty, we used a pseudo-cohort approach to explore birth cohort-related patterns based on GLOBOCAN 2022. Exposure to H. pylori was associated with a 1.59-fold increased risk of CRC (95% CI 1.36 to 1.87), consistent across most subgroups. In limited observational studies, H. pylori eradication was associated with a reduced risk of CRC, but only after 10 years of follow-up. Globally, under the pooled risk-attribution model based on estimates from 43 studies, an estimated 22.0% (95% UI 14.7% to 29.4%) of CRC cases were potentially related to H. pylori exposure; corresponding estimates were lower when restricted to population-based and cohort studies (n=14). Higher H. pylori-related burdens were observed in settings with lower CRC incidence and increased with rising H. pylori prevalence. Exploratory pseudo-cohort patterns suggested higher ERPs in later birth cohorts, while absolute case counts remained relatively stable. H. pylori exposure may meaningfully contribute to global CRC burden, with the extent of preventable burden dependent on the causal nature and other modifying variables related to H. pylori exposure (eg, timing, duration). This underscores the importance of well-designed randomised clinical trials and other prospective investigations evaluating the impact of H. pylori and its eradication on CRC risk, as well as potential modifying factors.

Pharmacological cancer risk reduction has received far less investment than therapeutic oncology and only a few agents have entered routine practice. Understanding the predictors of positive outcomes of previous trials and issues faced is critical to future developments. This systematic review (PROSPERO CRD420250650276) included all phase III randomised controlled trials enrolling cancer-free adults over the past 45 years, evaluating pharmacological agents and whose primary or major secondary endpoint was directly related to cancer risk reduction. To predict trials' 'success', defined here as meeting the prespecified cancer risk reduction-related endpoint within the planned timeline, we used the Least Absolute Shrinkage and Selection Operator followed by multivariable logistic regression. Ninety-two trials comprising 659 904 participants were included, of which 46 (50.0%) met their primary endpoint. Success rates varied by therapeutic class: vitamins (9 of 38, 23.7%), endocrine therapies (15 of 20, 75.0%), nonsteroidal anti-inflammatory drugs (8 of 13, 61.5%), human papillomavirus vaccines (8 of 9, 88.9%) and anti-infective agents (5 of 8, 62.5%). Proportionally, breast (76.5%), cervical (72.7%) and oesophagogastric (58.3%) cancer risk reduction trials had the highest success rates versus 23.7% for vitamins trials. Adherence was highest for vaccines [median 95%, interquartile range (IQR) 93%-96%] and lowest for endocrine therapies (median 70%, IQR 65%-78%). Major safety issues arising for a dozen of the drugs limited their approval (n = 5) and use. In the multivariable analysis, the odds of success increased for trials with pharmaceutical sponsorship [odds ratio (OR) 5.30, 95% confidence interval (CI) 1.01-35.77] and decreased for non mechanism-specific drugs and for studies with lower pretrial evidence (OR 0.30, 95% CI 0.10-0.90). Although half of the pharmacological cancer risk reduction trials conducted so far have shown positive results, only a handful have led to regulatory approval. Trial success was driven by more targeted strategies and strong preliminary evidence, underscoring the need for mechanism-driven, strong-evidence development pathways in cancer risk reduction.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide. Epidemiological evidence indicates that MASLD is associated with an increased risk of developing colorectal cancer (CRC). MASLD and CRC share many common risk factors and pathophysiological mechanisms, but an optimal strategy for identifying and managing CRC risk in individuals with MASLD remains lacking. This study aimed to achieve consensus on the risk of CRC in individuals with MASLD. A Delphi survey was conducted by a multidisciplinary panel of 35 international experts from diverse medical fields across Asia, Europe, North America, South America, Oceania and Africa. Experts evaluated 17 statements across three domains: epidemiology, pathogenesis and management. Consensus was achieved on all 17 statements. MASLD is associated with an increased risk of CRC, and metabolic burden further increases this risk. Furthermore, the severity of MASLD is associated with worse outcomes in patients with MASLD and CRC. The gut-liver axis and gut dysbiosis play key roles in the development of MASLD and CRC, while leptin and adiponectin may also be involved. Weight loss with lifestyle interventions, early CRC screening, bariatric surgery and use of GLP-1 receptor agonists are highlighted as potential risk-reduction strategies. The expert panel emphasises the need for greater clinical vigilance for CRC among individuals with MASLD. This consensus supports a paradigm shift towards earlier, risk-adapted screening and integrated metabolic management to reduce the burden of CRC in the MASLD population.

Influenza vaccination may confer benefits that extend well beyond seasonal protection against respiratory infection: reduced cardiovascular morbidity and mortality, lower dementia incidence, fewer cardio-renal complications, improved survival in the very old, and emerging signals in oncology and diabetes. Although vulnerable to confounding and evidence in adults aged ≥75-80 years and in frail populations remains scarce, their magnitude, cross-organ consistency and apparent dose-response suggest that protection is not explained solely by prevention of infection, but points to a shared upstream mechanism: modulation of chronic inflammation. Recent single-cell multiomic studies provide a plausible substrate: inactivated influenza vaccine induces persistent epigenetic remodelling in monocytes and myeloid dendritic cells, lasting up to six months,and, consistent with a regulatory recalibration of innate reactivity, termed trained tolerance. This myeloid axis is also central to inflammaging, whose clinical expression in older people is frailty. We review multiomic, preclinical and epidemiological evidence supporting a framework in which influenza vaccination may exert effects beyond pathogen-specific protection. Murine models provide causal evidence that vaccination can modify vascular, neurodegenerative and tumour pathology through systemic immune mechanisms. We position these findings alongside heterologous effects of other vaccines and examine their relevance to chronic inflammation. Although innate immune reprogramming involves pathways shared with inflammaging, a direct effect on chronic low-grade inflammation remains unproven. Key uncertainties including healthy-vaccinee bias, the absence of frailty stratification and the age discordance between mechanistic and clinical evidence are discussed.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening has become a central technology in functional genomics, enabling genome-scale interrogation via pooled perturbations. Early CRISPR screens employed survival or simple phenotypic readouts to identify essential genes and drug resistance mechanisms. However, as biological questions have shifted toward understanding regulatory networks, cellular heterogeneity, and context-dependent gene functions, there has been increasing demand for screening strategies capable of capturing complex cellular phenotypes beyond cell fitness. Recent advances in single-cell sequencing, high-content imaging, and spatial transcriptomics have expanded the resolution of CRISPR screening by enabling multidimensional phenotypic characterization following genetic perturbation. By integrating pooled perturbations with diverse readouts, these approaches systematically map targeted gene edits to transcriptional states, cellular phenotypes, and microenvironmental contexts. Meanwhile, innovations in library design, delivery, and computational pipelines have further improved the robustness and interpretability of high-content screening platforms. This review synthesizes the methodological evolution of CRISPR screening, emphasizing advances in perturbation strategies, delivery systems, and multimodal readouts. Representative applications spanning oncology, immunotherapy, developmental biology, neurobiology, and infectious diseases are delineated to demonstrate refined gene network annotations. Additionally, existing technical bottlenecks, such as scalability, cost constraints, and in vivo limitations, are critically assessed. Finally, future directions are proposed to facilitate the development of precise medicine.

Intestinal intraepithelial lymphocytes (IELs), including conventional CD8αβ T resident memory (Trm) cells and unconventional CD8αα T cells, promote tissue integrity. Here, we studied the G-protein coupled receptor signals regulating IEL positioning, homeostasis, and function. Deficiency in heterotrimeric G-protein subunit Gα13 or its effector Arhgef1 caused an intestine-specific loss of all types of CD8+ TCRαβ and TCRγδ IELs. Gα13-deficient IELs exhibited restricted intraepithelial movement and impaired maturation. Induction of intestinal CD8αβ+ Trm cells upon infection was intact in the absence of Gα13-signaling, but the cells had poor access to the villous niche and defective survival that could be rescued by increasing TGF-β or interleukin (IL)-15. In vivo CRISPR-Cas9 screening identified GPR132 as a Gα13-coupled receptor that regulates CD8αβ+ IEL homeostasis and migration to lysophosphatidylcholine. Mice bearing Gα13-deficient T cells suffered more severe colitis and increased colorectal tumor growth. The selective requirement for Gα13 signaling for IEL positioning and survival in the villous niche has implications for therapeutic intervention.

Although studies of tumor invasion have mainly emphasized the evolution of genetic and epigenetic heterogeneity, cellular behaviors also depend on the physical microenvironment. Yet, the tumor microenvironment is both complex and continuously remodeled, making it hard to rigorously test its causal influence on tumor dissemination. Here, we adopted a reductionist approach to studying tumor cell invasion in microengineered environments of tunable patterned geometries. We find that not only the presence of obstacles but more unexpectedly their spatial disorder causes a drastic shift from a collective to a single-cell mode of invasion-comparable in strength to loss of cell-cell adhesion. Combining live-imaging and perturbation experiments with minimal biophysical modeling, we demonstrate that cell dissemination results both from local geometrical constraints and a global integration of spatial disorder over time. We identify generic universality classes of invasion dynamics dependent on environmental geometry, enabling us to identify quantitative physical principles for tumor dissemination.

Most cancer therapies target genetic alterations driving tumor growth, but many drivers are undruggable or rare, limiting their therapeutic reach. Here, we demonstrate that amplified genes encoding cell surface proteins provide a rich, cancer-driver-agnostic source of targets. We identify MPZL1 (myelin protein zero-like 1), amplified in up to 75% of patients with certain solid tumor types, as abundantly expressed on the surface tumor cells across diverse cancer types while being largely absent from healthy tissues, offering a favorable therapeutic window. We develop a monoclonal antibody targeting MPZL1's extracellular domain and engineer chimeric antigen receptor (CAR)-T cells that selectively eliminate MPZL1-positive cancer cells in vitro. These CAR-T cells exhibit antitumor activity in human xenograft, autochthonous mouse, and patient-derived tissue explant preclinical models. This work establishes MPZL1 as a viable CAR-T cell target and provides a generalizable framework for exploiting amplified cell surface receptors as broadly applicable therapeutic targets.

Accumulating evidence supports the important role played by the gut microbiota in controlling antitumor immune responses that impact tumor development. Extensive studies of bacterial species known to impact tumor growth have identified metabolites, produced by either bacteria or the host, that may alter efficacy of chemo- and/or immune-based therapies. Here, we summarize our current knowledge of those metabolites and the related bacterial species that influence activities linked with antitumor immunity, including epigenetic changes, the aryl hydrocarbon receptor signaling, cytokine and chemokine production, Janus kinase/signal transducer and activator of transcription signaling, and toll-like receptor signaling. We focus on specific metabolites, produced in the gut microbiome, which can alter molecular pathways associated with antitumor immunity, findings that warrant further evaluation in preclinical or clinical settings.

Canonical and noncanonical autophagic processes are integrated with innate and adaptive immunity and sterile or pathogen-induced inflammation. In canonical autophagy, double-membrane autophagosomes modified by ubiquitin-like ATG8 proteins in a process termed membrane atg8ylation sequester and eliminate intracellular targets such as invading microbes, defunct organelles, aggregates, and inflammatory molecules. Recently, a plethora of noncanonical processes that entail membrane atg8ylation of various intracellular organelles other than autophagosomes have been linked to immunity. This has led to confounding interpretations and conflation of diverse processes as autophagy. Here, we posit that these are divergent manifestations of a common ancestral homeostatic process of membrane atg8ylation and provide an overview of how they affect immunity and inflammation. These relationships are evident in model organisms and are reflected in human genetic predispositions to diseases with immune components. The membrane atg8ylation pathways affect acute and chronic inflammation, infections, autoimmunity, cancer, neurodegeneration, metabolic syndrome, diabetes, and other disorders.

Treatment with adoptively transferred T cells is challenged by limited longevity of therapeutic cells within tumors. To enhance the durability of anti-tumor T cell products, we have created T cell receptors (TCRs) with built-in co-stimulatory molecules. We observed that TCRs coupled to ICOS mediated exceptionally long-term responses, including delay of tumor recurrence and cures in a mouse melanoma model. TCR:ICOS T cells showed enhanced and antigen-specific production of inflammatory cytokines, enrichment for a stem-like state and resistance to exhaustion. TCR:ICOS-mediated activation of PI3K and NFκB, yet restrained activation of AKT. Genetic ablation of the ICOS-PI3K pathway neutralized the long-term anti-tumor effects. To translate TCR:ICOS to human T cells, we identified a single amino acid change in the cytosolic tail which enabled functional surface expression without proneness to TCR mispairing nor competition for CD3. Notably, the optimized receptor sustained functional performance of human T cells upon repeated stimulation across multiple tumor antigens. Collectively, we present a novel and uniformly applicable TCR:ICOS format that supports fitter T cell products for adoptive cell therapy.

Anthracycline-induced cardiotoxicity (AIC) limits life-saving chemotherapy and is driven by early metabolic remodeling. The nuclear receptor ERRα (estrogen-related receptor α) is a master regulator of cardiac energy metabolism, but the temporal dynamics of its downregulation, its causal role in AIC pathogenesis, and whether it can be pharmacologically activated to confer protection remain undefined. We performed temporal protein analysis in a porcine AIC model. Using cardiomyocyte-specificgain- and loss-of-function mouse models, we assessed the causal role of ERRα. Mechanistic studies included ChIP-qPCR, reporter assays, and microscale thermophoresis to investigate the natural compound formononetin. Human breast cancer patient-derived organoids were used to evaluate anticancer activity. ERRα expression was selectively downregulated in AIC pig hearts and cardiac tissue from chemotherapy-treated patients. Temporal analysis in pigs revealed that ERRα reduction occurred at the subclinical (6-week) stage, preceding overt cardiac dysfunction. Cardiomyocyte-specific ERRα overexpression activated mitochondrial gene programs, enhanced fatty acid oxidation, and preserved systolic function after doxorubicin challenge, whereas ERRα knockdown exacerbated bioenergetic failure and cardiac dysfunction. Through drug screening, we identified formononetin as a potent and selective ERRα agonist. Formononetin enhanced ERRα transcriptional activity, improved mitochondrial metabolism, and protected against AIC in both murine and porcine models. Mechanistically, ChIP-qPCR demonstrated increased ERRα occupancy at target gene promoters, and microscale thermophoresis confirmed direct binding of formononetin to the ERRα/PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) complex, indicating allosteric stabilization. Finally, in human breast cancer patient-derived organoids, formononetin alone reduced viability and proliferation, and combined with doxorubicin further enhanced antitumor efficacy. ERRα downregulation is a causal early event in the pathogenesis of AIC. Formononetin acts as a first-in-class selective ERRα activator that improves cardiac metabolism and function while retaining anticancer activity, supporting its potential as a dual-action cardioprotective agent during anthracycline therapy.

Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology1. Here we dissect the mutational processes shaping the genomes of 959 donors from the Pan Prostate Cancer Group and assess their clinical relevance. By integrating de novo extracted single-base substitution, insertion-deletion and copy-number signatures with six novel complex structural variant signatures, we identify eight integrated mutational footprints (IMFs) that collectively explain the mutational processes in 85% of primary prostate cancer genomes. IMFs were strongly influenced by regional biases in the genome, most prevalently androgen receptor-mediated mutagenesis and replication stress. Four IMFs, present in 37% of primary tumours, were significantly associated with shorter time to metastasis. These included reactive oxygen-species-driven mutagenesis and both canonical and non-canonical homologous recombination deficiency, the latter being enriched in patients of African ancestry. Extending to the metastatic setting, we found that IMFs predicted sensitivity to androgen receptor pathway inhibitors. Taken together, our study delineates the aetiologies and mutational processes that drive the genomic and clinical heterogeneity of prostate cancer, introduces IMFs as a unifying framework, and highlights their potential to improve both risk stratification and biomarker-guided treatment selection.

Evidence regarding the effects of air pollution on bone damage remains limited and inconclusive. We aimed to investigate the individual and combined associations of long-term exposure to ambient air pollutants with fracture risk and bone mineral density (BMD). This study included 490,172 participants from the China Kadoorie Biobank who were free of prior fractures at baseline, among whom 32,545 received calcaneus BMD measurement using quantitative ultrasound in the second or third resurveys. Annual mean concentrations of particulate matter with diameters≤ 2.5μm (PM2.5), ≤ 10μm (PM10), nitrogen dioxide (NO2), and warm-season ozone (O3) were assigned to participants based on the geographic locations of recruitment clinics in their communities, using 1 × 1 km resolution. Incident fracture cases were defined as the first occurrence of fracture at any anatomical site, excluding those least likely due to osteoporosis and most likely due to severe trauma or cancer. Time-varying Cox proportional hazard models and linear mixed models were used to examine individual associations between air pollutant exposure and incident fracture risk, and longitudinal changes in BMD, respectively. Principal component analysis and quantile-based g-computation were applied to evaluate the combined effects of air pollutants and the relative contributions of each pollutant. Mediation analyses were performed to investigate the potential mediating role of BMD in the associations between pollutant and fracture risk. During a median follow-up of 12.0 years, 15,614 fractures were identified. Long-term exposure to PM2.5 and warm-season O3 was associated with an increased risk of any fracture, with hazard ratios (HRs) and 95% confidence intervals (CIs) of 1.09 (1.05, 1.13) and 1.08 (1.04, 1.12), respectively, per 10 µg/m3 increase in concentration. For each unit increase in the principal component score for air pollutants, the HR (95%CI) for any fracture was 1.08 (1.03, 1.13). PM2.5 contributed most to the elevated fracture risk (70%), followed by warm-season O3 (30%). Higher levels of air pollution were associated with lower BMD, with BUA, SOS, SI, and T-score lowering by 0.263 (95%CI: 0.220, 0.305), 0.265 (0.225, 0.306), 0.299 (0.264, 0.334), and 0.311 (0.274, 0.347) (in units of standard deviation) for per principal component score increment, respectively. The decline in the latter three BMD measures accounted for 5.80-8.59% of the association between pollutants and fracture risk. Long-term co-exposure to PM2.5, PM10, NO2, and warm-season O3 was associated with lower BMD and increased fracture risk, with reduced BMD potentially acting as a modest partial mediator. PM2.5 consistently exhibited the greatest contribution to the associations between air pollutants and both fracture risk and BMD. Our findings suggest that adherence to fine particulate matter control and enhanced pollutant synergism may play an important role in bone health promotion in aging populations.

Glioblastoma (GBM) is traditionally viewed as disrupting brain network connectivity. Recent evidence of tumor-neuron synaptic interactions suggests gliomas may actively engage with the brain. We hypothesized that GBM tumors contain functionally distinct intratumoral subregions that differentially couple with resting-state networks (RSNs) and carry prognostic significance. We applied fuzzy c-means clustering to resting-state fMRI data from 190 GBM patients to identify and count the number of intratumoral functional subregions. We used the participation ratio, a PCA-derived measure of signal dimensionality, as a continuous variable complement to cluster number. Cluster-level BOLD time series were correlated with seven canonical RSNs and compared to tumor location-matched voxels in 347 healthy subjects. Associations with survival and preoperative seizures were evaluated using Kaplan-Meier analysis, restricted mean survival time (RMST), multivariable Cox proportional hazards modeling, and multivariable logistic regression. Fifty-two of 190 GBMs exhibited multiple intratumoral functional clusters. Multi-cluster tumors were associated with longer survival and higher seizure prevalence. Elevated RSN coupling was more prevalent in multi-cluster tumors as compared to single-cluster tumors, with elevated coupling strongly predicting multi-cluster status. Distinct clusters often showed preferential coupling to different RSNs. A subset of GBM contains functionally distinct subregions that selectively engage large-scale brain networks, a pattern associated with favorable survival and increased seizure risk. These findings support a model in which certain tumors function as active participants within neurovascular networks, indicating a novel network-integrated subtype of GBM with implications for prognosis and disease staging.

Smoking has been associated with lower risks of Parkinson disease (PD) in epidemiological studies, but the underlying mechanisms remain poorly elucidated. To investigate the association of exhaled carbon monoxide (CO) with risk of PD. This nationwide prospective cohort study leveraged data from the China Kadoorie Biobank across 10 geographically diverse areas in China. A total of 512 724 adults aged 30 to 79 years were recruited between June 2004 and July 2008. Prospective analyses were restricted to first events occurring between ages 40 and 94 years and before January 1, 2019. Data were analyzed from May 2025 to March 2026. Self-reported smoking status and measured exhaled CO. During approximately 12 years' follow-up, 1131 individuals with PD and 2949 with other neurodegenerative diseases were recorded through linkage to national death and disease registries and the health insurance system. Cox regression was used to estimate adjusted hazard ratios (HRs) for associations of smoking and, among individuals who never smoked, exhaled CO levels with PD, other neurodegenerative diseases, and several known smoking-related diseases. Covariates included sociodemographic characteristics, lifestyle factors, and other confounders (ie, solid fuel use and passive exposure to smoking). Among the 512 701 participants included in the main analyses, the mean (SD) age was 52 (11) years and 302 041 (58.9%) were female. Overall, 156 650 male individuals (74.5%) and 9944 female individuals (3.3%) ever smoked regularly, with mean exhaled CO levels higher among those who regularly smoked (11.1 ppm) than those who never smoked (3.5 ppm), those who occasionally smoked (3.8 ppm), and those who formerly smoked regularly (3.7 ppm). Regular smoking was significantly associated with elevated risks of lung cancer, ischemic heart disease, stroke, and all-cause mortality but with lower risk of PD (adjusted HR, 0.70; 95% CI, 0.62-0.79). In individuals who never smoked, higher exhaled CO levels were associated with lower HRs of PD (n = 675) in a broadly dose-dependent manner (exhaled CO <2.0 ppm: 1.00 [95% CI, 0.85-1.18]; 2.0 to <3.0: 0.85 [95% CI, 0.73-0.99]; 3.0 to <5.0: 0.62 [95% CI, 0.53-0.73]; 5.0 to <11.5: 0.68 [95% CI, 0.56-0.83]; ≥11.5: 0.65 [95% CI, 0.45-0.92]; P for trend < .001) but were not associated with risks of smoking-related diseases or other neurodegenerative diseases. The associations with PD were more pronounced in female individuals who never smoked. Similar exhaled CO-PD associations were found in those who regularly smoked. Among individuals who never smoked, higher exhaled CO levels were associated with lower PD risk. These findings demonstrate a potentially protective role of CO in PD etiology, which help explain the association between smoking and PD observed in this and other epidemiological studies and support ongoing clinical trials of CO in the treatment of PD.

Mitochondrial quality control is essential for maintaining cellular and tissue homeostasis. Mitophagy, the selective autophagic removal of damaged mitochondria, is a central component of this process, and defects in mitophagy are increasingly linked to neurodegeneration, cardiovascular disease, cancer, and inherited mitochondrial disorders. Ubiquitin-dependent tagging of outer mitochondrial membrane proteins is a major mechanism for marking damaged mitochondria for clearance; however, recent advances reveal that mitochondrial deubiquitinases (DUBs) shape ubiquitin signaling at damaged mitochondria, thereby influencing the efficiency and selectivity of mitochondrial turnover. Moreover, DUBs are emerging as context-dependent editors of the mitochondrial ubiquitin code that link mitophagy to disease pathogenesis and therapeutic intervention. Here, we synthesize current understanding of mitochondrial DUBs in physiology and disease and discuss emerging pharmacological strategies to guide the development of mitophagy-targeted therapeutics.

In this issue of Cancer Cell, Luo et al. report an ensemble approach that integrates five pretrained pathology foundation models into a slide-level representation to exploit their complementary information, yielding improvements in tumor subtyping, biomarker, and therapy-response prediction. This shows the potential of ensemble and multimodal approaches in computational pathology.

Cancer hazard identification is the first step in preventing cancer. Robust and transparent methods for rigorous interrogation of published research are vital for a high-quality assessment of the scientific evidence resulting in cancer hazard identification. The National Toxicology Program publishes cancer hazard assessments for possible listing in the Report on Carcinogens (RoC), which are conducted using a four-part systematic review (SR) process described in the RoC Handbook. This Handbook provides guidance for developing a substance-specific evaluation framework, assessing study informativeness, evaluating and integrating data across studies within each evidence stream (e.g., human, experimental animal, and mechanistic studies) and then integrating across evidence streams to reach a cancer hazard conclusion. The recently updated RoC Handbook incorporates advances in SR methods and provides an updated suite of tools, approaches, and resources to ensure scientific rigor, transparency, and confidence in conclusions reached in cancer hazard evaluations. The most significant advancements include a new fit-for-purpose SR strategy and guidance for assessing and integrating evidence from mechanistic studies, including read-across approaches, and clearer approaches for integrating evidence across evidence streams to reach causal conclusions. We also added toolkits for determining the informativeness of human, animal cancer, and mechanistic studies, and resources related to literature search strings, exposure assessment, and information on biomarkers and assays for the Key Characteristics of Carcinogens. These innovations have significantly enhanced the transparency and scientific integrity of RoC cancer hazard assessments and can be used by the scientific community for their own assessments.

Keith T. Flaherty, MD, who began a 1-year term as president of the American Association for Cancer Research in April 2026, spoke with Cancer Discovery's Suzanne Rose about his work, what he sees as the most exciting advances in cancer research, and his vision for the future.

Circulating tumor DNA (ctDNA) is a key component of liquid biopsy and has emerged as one of the most promising biomarkers. However, the clinical value of ctDNA depends directly on the biological mechanisms that govern its release and persistence within the circulation. In this review, we provide an overview of the current understanding of ctDNA biology and its clinical implications. We describe the mechanisms of ctDNA shedding and clearance, as well as the factors that influence its dynamic balance. We discuss the role of ctDNA as a tumor biomarker, but also the hypothesis that ctDNA may also play an active role in tumor progression. A better understanding of these mechanisms is essential for accurately interpreting ctDNA analyses, optimizing their clinical use, and facilitating their integration into personalized cancer patient management.